Quinazolines and azaquinazolines as dual inhibitors of ras/raf/mek/erk and pi3k/akt/pten/mtor pathways

ABSTRACT

The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R 4 , and R 6  to R 8′  are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer.

BACKGROUND

Recent advances in understanding the molecular mechanisms of cancer haveled to the discovery and development of anticancer therapeutic agentstargeting important signaling pathways. These agents typically providegreater therapeutic benefit to the patients with lesser toxicity ascompared to the conventional cytotoxic agents. However, patients oftenface the inevitable reality of recurrence of the cancer due to acquiredresistance to the targeted therapeutic agents. There is a great unmetmedical need to preempt or address such acquired resistance to cancertherapies.

Two pathways, RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR, play an importantrole in the initiation and progression of tumors. Recently, there hasbeen intense activity to discover and develop new agents targeting thesetwo pathways. The RAS/RAF/MEK/ERK pathway is known to be dysregulatedthrough genetic mutations in RAS, RAF or MEK genes, which leads toincreased cell proliferation and angiogenesis. These mutations have beenfound in wide variety tumors. Inhibition of any of these targets wasfound to effectively inhibit the growth of tumors either in preclinicalmodels or in humans. Recently, several compounds have been discoveredwhich selectively inhibit one of these targets, RAF kinase. Theinhibitors of RAF kinase include vemurafenib, dabrafenib, XL-281,LGX-818, CEP-32496 and ARQ-736. Vemurafenib is now an FDA-approved drugfor treating the metastatic melanoma patients. Other compounds are invarious stages of clinical development, including MEK-162, selumetinib,refametinib, E-6201, pimasertib, WX-554 and GDC-0973. Although severalcompounds targeting RAS protein have been identified, thus far none ofthem have been approved by the FDA.

Similar to the RAS pathway, PI3K/AKT/mTOR pathway also plays animportant role in tumors, specifically in promoting the tumor cellsurvival and proliferation. This pathway is dysregulated through geneticchanges in PI3K, AKT and PTEN genes. Several proteins in this pathwayhave been subjected for the drug discovery efforts, leading to theidentification of many inhibitors against PI3K, AKT and mTOR proteins,and some of these inhibitors (such as temsirolimus and everolimus) havebeen approved by the FDA for various indications. Other inhibitors ofthe PI3K pathway are in various stages of clinical development,including the PI3K inhibitors GDC-0941, PX-866, XL-147, BKM-120, and BAY80-6946, the mTOR inhibitors deforolimus, OSI-027 and AZD8055, thePI3K/mTOR dual inhibitors BEZ-235, XL-765, GDC-0980, GSK-2126458,PKI-587, and PF-04691502 and the AKT inhibitors MK-206, GDC-0068,GSK2636771, afuresertib, rigosertib and CLR-1401.

Despite some promising initial results in humans, several of theabove-mentioned compounds are not able to provide a durable response dueto the acquired resistance rendered by the activation of the alternativepathway(s) in the targeted cancer cells. For example, the inhibition ofthe PI3K pathway with agents such as temsirolimus leads to thesubsequent activation of the RAS pathway, resulting in tumors which donot respond to this agent. Conversely, inhibition of RAS pathway leadsto the activation of PI3K pathway. Preclinical data has demonstratedthat the combinatorial inhibition of both pathways simultaneously givesa greater and more durable efficacy in tumor growth inhibition. Thesefindings clearly indicate a need for combination therapies to overcomethe acquired clinical resistance to single-pathway inhibitors. Severalclinical trials with different combinations of two agents eachinhibiting one of these two pathways have already been initiated. Themost advanced combination clinical trial is in Phase II with AZD6244 (aMEK inhibitor) and MK2206 (an AKT inhibitor). However, combining twodifferent agents in this manner can produce the significantdisadvantages of added toxicity and higher cost.

Therefore, there is an unmet medical need to identify compounds withdual inhibitory activity against both pathways.

BRIEF DESCRIPTION OF THE FIGURES

The FIGURE is a Western blot showing inhibition of pERK, p S6RP,pAKT-S473 and pAKT-T308 in mouse xenograft RKO tumor cell lysates by acompound described herein.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I), wherein X, Y,T, R⁴, and R⁶ to R^(8′) are defined herein, a composition containing thecompound of formula (I), and a kit containing the compound of formula(I).

Also provided are methods for co-regulating RAS/RAF/MEK/ERK andPI3K/AKT/PTEN/mTOR which include administering a therapeuticallyeffective amount of a compound to a patient. In one embodiment,co-regulation includes inhibiting the RAS/RAF/MEK/ERK pathway. Inanother embodiment, co-regulation includes inhibiting thePI3K/AKT/PTEN/mTOR pathway. In a further embodiment, co-regulationincludes inhibiting RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways.

A method for treating a condition treatable by inhibiting theRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways is further provided.This method includes administering a therapeutically effective amount ofa compound of formula (I) to a patient.

Further provided is a method for treating a disease characterized by anabnormal cellular proliferation resulting from dysregulatedRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. The method includesadministering a therapeutically effective amount of a compound offormula (I) to a patient. In one embodiment, the disease is cancer.

Other aspects and advantages of the invention will be readily apparentfrom the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention therefore provides compounds which inhibit boththe RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. In one embodiment,the compounds target B-RAF and mTOR. In another embodiment, thecompounds target B-RAF and PI3K. In a further embodiment, the compoundstarget B-RAF, mTOR and PI3K. Such a compound useful herein isencompassed by formula (I):

In this structure, X is CH or N, Y is H, optionally substituted C₁-C₆alkyl, OR¹ or NR²R³, and T is H or C₁-C₆ alkoxy.

R¹ is optionally substituted C₁-C₆ alkyl, optionally substituted (C₁-C₆alkyl)OH, optionally substituted (C₁-C₆ alkyl)OC₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₆ alkyl)NH₂,optionally substituted (C₁-C₆ alkyl)CO₂H, or optionally substituted(C₁-C₆ alkyl)CONH₂.

R² and R³ are joined to form an optionally substituted heterocycle.

R⁴ is optionally substituted morpholine. In one embodiment, R⁴ ismorpholine. In another embodiment, R⁴ is substituted morpholine. In afurther embodiment, R⁴ is morpholine substituted by C₁-C₆ alkyl. In yetanother embodiment, R⁴ is:

R⁷ is optionally substituted aryl, optionally substituted C₁-C₆ alkyl,or optionally substituted heteroaryl; R⁸ is H or halogen; and R^(8′) ishalogen. In one embodiment, R⁷ is an optionally substituted aryl. Inanother embodiment, R⁷ is phenyl substituted by one of more halogen. Ina further embodiment, R⁷ is

In still another embodiment, R⁷ is optionally substituted C₁-C₆ alkyl.In yet a further embodiment, R⁷ is C₁-C₆ alkyl optionally substituted byone or more F. In another embodiment, R⁷ is i-propyl, i-butyl, n-propyl,ethyl, n-butyl, CH₂CH₂CH₂F, or CH₂CH₂CF₃. In still a further embodiment,R⁷ is optionally substituted heteroaryl. In another embodiment, R⁷ isthiophene.

R⁶ is in formula (I) is an optionally substituted aryl or optionallysubstituted heteroaryl. In one embodiment, R⁶ is

wherein M is N or CR¹⁰; Q is N or CR¹³; Z is N or CR¹⁴; R¹⁰ is H, C₁-C₆alkyl, halogen, CN or CF₃; R¹² to R¹⁴ are, independently, H, halogen,C₁-C₆ alkyl, or CF₃; R¹⁷ is NHC(O)NHNR⁹, H, C₁-C₆ alkyl, (C₁-C₆alkyl)-NH₂, (C₁-C₆ alkyl)-OH, (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), CO(C₁-C₆alkyl) or SO₂(C₁-C₆ alkyl); or R¹³ and R¹⁷ or R¹⁴ and R¹⁷ are joined toform an optionally unstaturated ring; and R⁹ is C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, or heteroaryl. In another embodiment, R⁶ is

wherein Z is CH or N; and R⁹ is C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, orheteroaryl. R⁹ may be CH₃, CH₂CH₂OH, or pyridine-4-yl, among others. Ina further embodiment, R⁶ is an optionally substituted pyrimidine,optionally substituted pyridine, optionally substitutedpyrrole[2,3-b]pyridine, optionally substituted indazole or optionallysubstituted benzimidazole. In still another embodiment, R⁶ is

wherein R¹⁰ is H, C₁-C₆ alkyl or trifluoromethyl; and R¹⁷ is H, C₁-C₆alkyl, (C₁-C₆ alkyl)-NH₂ or (C₁-C₆ alkyl)-OH. In yet a furtherembodiment, R⁶ is

wherein R¹⁰, R¹² and R¹³ are, independently, H, halogen, C₁-C₆ alkyl, CNor CF₃; and R¹⁷ is H, C₁-C₆ alkyl, (C₁-C₆ alkyl)-NH₂ or (C₁-C₆alkyl)-OH; or R¹³ and R¹⁷ are joined to form an optionally unsaturatedring. In another embodiment, R⁶ is

wherein R¹⁰ is H, C₁-C₆ alkyl, halogen, CN or CF₃; R¹² is H or halogen;R¹³ is H, halogen or C₁-C₆ alkyl; and R¹⁷ is H, C₁-C₆ alkyl, (C₁-C₆alkyl)-NH₂ or (C₁-C₆ alkyl)-OH; or R¹³ and R¹⁷ are joined to form anoptionally unsaturated 5-membered ring. In still a further embodiment,R⁶ is

In yet a further embodiment, R⁶ is

wherein R¹⁵ is C₁-C₆ fluoroalkyl or C₁-C₆ hydroxyalkyl. In anotherembodiment, R⁶ is or

In still a further embodiment, R⁶ is

and is bound through any carbon atom. In yet another embodiment, R⁶ is

Representative “pharmaceutically acceptable salts” include but are notlimited to water-soluble and water-insoluble salts. In one embodiment,the salt is of a base. The salt can be of a base selected from, e.g.,alkali metal salt bases such as sodium, lithium, or potassium andorganic bases, such as ammonium, mono-, di-, and trimethylammonium,mono-, di- and triethylammonium, mono-, di- and tripropylammonium,ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpholinium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-,di- and triethanolammonium, ethyl diethanolammonium,n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium,phenylmonoethanolammonium, among others.

In another embodiment, the salt is of an acid. The salt can be of anacid selected from, e.g., among acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,trifluoroacetic, and camphorsulfonic. Optionally, a composition of theinvention may contain both a pharmaceutically acceptable salt and thefree base form of a compound of the invention.

In a further embodiment, a compound of the invention may be a solvate.As used herein, a solvate does not significantly alter the physiologicalactivity or toxicity of the compounds, and as such may function aspharmacological equivalents to non-solvate compounds of the invention.The term “solvate” as used herein is a combination, physical associationand/or solvation of a compound of the present invention with a solventmolecule. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instances,the solvate can be isolated, such as when one or more solvent moleculesare incorporated into the crystal lattice of a crystalline solid. Thus,“solvate” encompasses both solution-phase and isolatable solvates.

Some compounds within the present invention possess one or more chiralcenters, and the present invention includes each separate enantiomer ofsuch compounds as well as mixtures of the enantiomers. Where multiplechiral centers exist in compounds of the present invention, theinvention includes each possible combination of chiral centers within acompound, as well as all possible enantiomeric mixtures thereof. Allchiral, diastereomeric, and racemic forms of a structure are intended,unless the specific stereochemistry or isomeric form is specificallyindicated. It is well known in the art how to prepare optically activeforms, such as by resolution of racemic forms or by synthesis fromoptically active starting materials.

The following definitions are used in connection with the compoundsdescribed herein. In general, the number of carbon atoms present in agiven group is designated “C_(x) to C_(y)”, where x and y are the lowerand upper limits, respectively. The carbon number as used in thedefinitions herein refers to carbon backbone and carbon branching, butdoes not include carbon atoms of the substituents, such as alkoxysubstitutions and the like. Unless indicated otherwise, the nomenclatureof substituents that are not explicitly defined herein are determined bynaming from left to right the terminal portion of the functionalityfollowed by the adjacent functionality toward the point of attachment.As used herein, “optionally substituted” means that at least 1 hydrogenatom of the optionally substituted group has been replaced.

“Alkyl” refers to a hydrocarbon chain that may be straight or branched,or to a hydrocarbon group that consists of or contains a cyclic alkylradical. In one embodiment, an alkyl contains 1 to 6 (inclusive) carbonatoms or integers or ranges there between (2, 3, 4, or 5). In anotherembodiment, an alkyl contains 1 to 5 (inclusive) carbon atoms or rangesthere between. In a further embodiment, an alkyl contains 1 to 4(inclusive) carbon atoms. In yet another embodiment, an alkyl contains 1to 3 (inclusive) carbon atoms. In still a further embodiment, an alkylcontains 1 or 2 carbon atoms. Examples of alkyl groups that arehydrocarbon chains include, but are not limited to, methyl, ethyl,propyl, butyl, pentyl, and hexyl, where all isomers of these examplesare contemplated. Examples of alkyl groups that consist of or contain acyclic alkyl radical include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, 3,3-dimethylcyclobutyl, (cyclopropyl)methyl,and (cyclopentyl)methyl. An alkyl can be unsubstituted or substitutedwith one or more groups including, without limitation, halogen, OH, NH₂,N(C₁ to C₃ alkyl)C(O)(C₁ to C₆ alkyl), NHC(O)(C₁ to C₆ alkyl), NHC(O)H,C(O)NH₂, C(O)NH(C₁ to C₆ alkyl), C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl),CN, C₁ to C₆ alkoxy, C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆alkyl), aryl, heteroaryl, NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆alkyl), OC(O)(C₁ to C₆ alkyl), optionally substituted heterocycle, andNO₂. In one embodiment, the substituted alkyl is CH₂OH.

“Alkoxy” refers to (alkyl)O, where the alkyl is optionally substitutedand is defined above. In one embodiment, an alkoxy contains 1 to 6(inclusive) carbon atoms or integers or ranges there between (2, 3, 4,or 5). In another embodiment, an alkoxy contains 1 to 5 (inclusive)carbon atoms or ranges there between. In a further embodiment, an alkoxycontains 1 to 4 (inclusive) carbon atoms. In yet another embodiment, analkoxy contains 1 to 3 (inclusive) carbon atoms. In still a furtherembodiment, an alkoxy contains 1 or 2 carbon atoms. Examples of alkoxyinclude, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.The alkyl radical of an alkoxy group can be unsubstituted or substitutedas defined above for “alkyl”.

“Hydroxyalkyl” refers to (alkyl)OH, where the alkyl is optionallysubstituted and is defined above. The OH moiety of the hydroxyalkyl maybe bound to any carbon atom, for example, any one of the internal carbonatoms or the terminal carbon atom of a hydrocarbon alkyl chain. In oneembodiment, a hydroxyalkyl contains 1 to 6 (inclusive) carbon atoms orintegers or ranges there between (2, 3, 4, or 5). In another embodiment,a hydroxyalkyl contains 1 to 5 (inclusive) carbon atoms or ranges therebetween. In a further embodiment, a hydroxyalkyl contains 1 to 4(inclusive) carbon atoms. In yet another embodiment, a hydroxyalkylcontains 1 to 3 (inclusive) carbon atoms. In still a further embodiment,a hydroxyalkyl contains 1 or 2 carbon atoms. Examples of a hydroxyalkylinclude, but are not limited to, CH₂OH, CH₂CH₂OH, CH(OH)CH₃,CH₂CH₂CH₂OH, CH₂CH(OH)CH₃, CH(OH)CH₂CH₃, C(OH)(CH₃)₂,(2-hydroxy)-cyclopentyl, (3-hydroxy)-cyclobutyl, and the like.

“Aryl” refers to an aromatic hydrocarbon group containing carbon atoms.In one embodiment, the aryl contains 6-10 carbon atoms, and is phenyl oris an aromatic or partly aromatic bicyclic group. In a furtherembodiment, the aryl is a phenyl group. In another embodiment, the arylis naphthyl (such as α-naphthyl or β-naphthyl),1,2,3,4-tetrahydronaphthyl, or indanyl. An aryl group can beunsubstituted or substituted with one or more groups including, withoutlimitation, halogen, OH, NH₂, N(C₁ to C₃ alkyl)C(O)(C₁ to C₆ alkyl),NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂, C(O)NH(C₁ to C₆ alkyl),C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), C₁ to C₆ alkyl, CN, C₁ to C₆alkoxy, C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl,heteroaryl, NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl),OC(O)(C₁ to C₆ alkyl), and NO₂. In one embodiment, an aryl issubstituted with one or more halogen, OH, CN, NH₂, C₁ to C₆ alkylamino,C₁ to C₆ alkyl substituted with OH, C₁ to C₆ alkoxy, C₁ to C₆ haloalkyl,OCF₃, SO₂(C₁ to C₆ alkyl), or NHSO₂(C₁ to C₆ alkyl). In anotherembodiment, an aryl is substituted with one halogen, OH, CN, NH₂, C₁ toC₆ alkylamino, C₁ to C₆ alkyl substituted with OH, C₁ to C₆ alkoxy, CF₃,OCF₃, SO₂CH₃, NHCOCH₃, or NHSO₂CH₃. In a further embodiment, an aryl issubstituted with one halogen, OH, CN, N(CH₃)₂, CH₂OH, OCH₃, OCF₃, CF₃,SO₂CH₃, NHCOCH₃, or NHSO₂CH₃.

“Halogen” refers to F, Cl, Br and I.

The term “heteroatom” refers to a sulfur, nitrogen, or oxygen atom.

“Heteroaryl” refers to a monocyclic aromatic 5- or 6-membered ringcontaining at least one ring heteroatom. In one embodiment, theheteroaryl contains 1 to 5 carbon atoms (inclusive) or integers orranges there between (2, 3, or 4). In a further embodiment, theheteroaryl contains 2 to 5 carbon atoms (inclusive). In anotherembodiment, the heteroaryl contains 3 to 5 carbon atoms (inclusive). Instill a further embodiment, the heteroaryl contains 4 or 5 carbon atoms.“Heteroaryl” also refers to bicyclic aromatic ring systems wherein aheteroaryl group as just described is fused to at least one other cyclicmoiety. In one embodiment, a phenyl radical is fused to a 5- or6-membered monocyclic heteroaryl to form the bicyclic heteroaryl. Inanother embodiment, a cyclic alkyl is fused to a monocyclic heteroarylto form the bicyclic heteroaryl. In yet a further embodiment, thebicyclic heteroaryl is a pyridine fused to a 5- or 6-membered monocyclicheteroaryl. In another embodiment, the bicyclic heteroaryl is apyrimidine fused to a 5- or 6-membered monocyclic heteroaryl. In yet afurther embodiment, the bicyclic heteroaryl is a pyridazine fused to a5- or 6-membered monocyclic heteroaryl. In still another embodiment, theheteroaryl ring has 1 or 2 nitrogen atoms in the ring. In a furtherembodiment, the heteroaryl ring has 1 nitrogen atom and 1 oxygen atom.In yet another embodiment, the heteroaryl ring has 1 nitrogen atom and 1sulfur atom. Examples of heteroaryl groups include, without limitation,furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole,isothiazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine,pyrrole, pyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, tetrazole,benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole,azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Aheteroaryl may be unsubstituted or substituted with one or more groupsincluding, without limitation, halogen, C₁ to C₆ alkyl, OH, C₁ to C₆hydroxyalkyl, C₁ to C₆ haloalkyl, NH₂, N(C₁ to C₃ alkyl)C(O)(C₁ to C₆alkyl), NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂, C(O)NH(C₁ to C₆alkyl), C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), CN, C₁ to C₆ alkoxy,C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl, heteroaryl,NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), OC(O)(C₁ to C₆alkyl), NH(C₁ to C₆ hydroxyalkyl), N(C₁ to C₆ hydroxyalkyl)₂,C(O)NH[—(C₁ to C₆ alkyl)-N(C₁ to C₆ alkyl)₂], C(O)NH[—(C₁ to C₆alkyl)-NH(C₁ to C₆ alkyl)], C(O)N(C₁ to C₆ alkyl)[-(C₁ to C₆ alkyl)-N(C₁to C₆ alkyl)₂] and NO₂. In one embodiment, a heteroaryl is substitutedwith one or more halogen, OH, CN, NH₂, C₁ to C₆ alkylamino, C₁ to C₆alkyl substituted with OH, C₁ to C₆ alkoxy, C₁ to C₆ haloalkyl, OCF₃,SO₂(C₁ to C₆ alkyl), NHCOCH₃, or NHSO₂(C₁ to C₆ alkyl). In anotherembodiment, a heteroaryl is substituted with one halogen, OH, CN,N(CH₃)₂, CH₂OH, OCH₃, OCF₃, CF₃, SO₂CH₃, NHCOCH₃, or NHSO₂CH₃.

“Heterocycle” refers to a monocyclic or bicyclic group in which at least1 ring atom is a heteroatom. A heterocycle may be saturated or partiallysaturated. In one embodiment, the heterocycle contains 3 to 7 carbonatoms (inclusive) or integers or ranges there between (4, 5, or 6). In afurther embodiment, the heterocycle contains 4 to 7 carbon atoms(inclusive). In another embodiment, the heterocycle contains 4 to 6carbon atoms (inclusive). In still a further embodiment, the heterocyclecontains 5 or 6 carbon atoms (inclusive). Examples of heterocyclesinclude, but are not limited, to aziridine, oxirane, thiirane,morpholine, thiomorpholine, pyrroline, pyrrolidine, azepane,dihydrofuran, THF, dihydrothiophene, tetrahydrothiophene, dithiolane,piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran,thiane, thiine, piperazine, homopiperazine, oxazine, azecane,tetrahydroquinoline, perhydroisoquinoline,5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane,2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane,3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane,7-oxa-2,5-diazabicyclo[2.2.2]octane,2,7-dioxa-5-azabicyclo[2.2.2]octane,2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane,3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane,3-oxa-8-azabicyclo[3.2.1]octan-8-yl,5,7-dioxa-2-azabicyclo[2.2.2]octane,6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,8-oxa-3-azabicyclo[3.2.1]octan-3-yl,2,5-diazabicyclo[2.2.1]heptane-5-yl, 6-azabicyclo[3.2.1]oct-6-yl,8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl,3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. Inanother embodiment, the heterocycle contains 1 or 2 nitrogen atoms. In afurther embodiment, the heterocycle contains 1 or 2 nitrogen atoms and 3to 6 carbon atoms. In yet another embodiment, the heterocycle contains 1or 2 nitrogen atoms, 3 to 6 carbon atoms, and 1 oxygen atom. In still afurther embodiment, the heterocycle is morpholine. In one embodiment,the heterocycle is morpholine and is substituted with one or more C₁ toC₃ alkyl. In another embodiment, the heterocycle is morpholine and 2carbons of the heterocycle are joined to form a 4- or 5-membered ring. Aheterocycle may be unsubstituted or substituted with one or more groupsincluding, without limitation, halogen, C₁ to C₆ alkyl, OH, NH₂, N(C₁ toC₃ alkyl)C(O)(C₁ to C₆ alkyl), NHC(O)(C₁ to C₆ alkyl), NHC(O)H, C(O)NH₂,C(O)NH(C₁ to C₆ alkyl), C(O)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), CN, C₁ toC₆ alkoxy, C(O)OH, C(O)O(C₁ to C₆ alkyl), C(O)(C₁ to C₆ alkyl), aryl,heteroaryl, NH(C₁ to C₆ alkyl), N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl),OC(O)(C₁ to C₆ alkyl), NH(C₁ to C₆ hydroxyalkyl), N(C₁ to C₆hydroxyalkyl)₂, C(O)NH[—(C₁ to C₆ alkyl)-N(C₁ to C₆ alkyl)₂],C(O)NH[—(C₁ to C₆ alkyl)-NH(C₁ to C₆ alkyl)], C(O)N(C₁ to C₆ alkyl)[-(C₁to C₆ alkyl)-N(C₁ to C₆ alkyl)₂] and NO₂. In one embodiment, aheterocycle is substituted with one or more halogen, OH, CN, NH₂, C₁ toC₆ alkylamino, C₁ to C₆ alkyl substituted with OH, C₁ to C₆ alkoxy, C₁to C₆ haloalkyl, OCF₃, SO₂(C₁ to C₆ alkyl), NHCOCH₃, or NHSO₂(C₁ to C₆alkyl). In another embodiment, a heterocycle is substituted with one F,OH, CN, NH₂, N(CH₃)₂, CH₂OH, OCH₃, OCF₃, CF₃, SO₂CH₃, NHCOCH₃, orNHSO₂CH₃.

“Optionally-substituted —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂CH₂—” refers to —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂CH₂— wherein 1 or 2 of the hydrogen atoms are replaced withOH, NH₂, NHCH₃, N(CH₃)₂, halogen, alkoxy, CF₃, OCF₃, or CN.

“C₁ to C₆ haloalkyl” refers to a C₁ to C₆ alkyl group, as defined above,wherein one or more of the C₁ to C₆ alkyl group's hydrogen atoms hasbeen replaced with F, Cl, Br, or I. Each substitution can beindependently selected from F, Cl, Br, or I. Representative examples ofa C₁ to C₆ haloalkyl group include, but are not limited to, CH₂F, CF₃,CH₂CF₃, and the like.

“Alkylsulfonyl” refers to an (alkyl)SO₂

group, which is bound through the SO₂ moiety. The alkyl group is definedand optionally substituted as described above. Examples of alkylsulfonylinclude, but are not limited to, CH₃SO₂, CH₃CH₂CH₂SO₂, CH₃CH(CH₃)SO₂,CH₃CH₂CH₂CH₂SO₂, CH₃CH(CH₃)CH₂SO₂, (CH₃)₃CSO₂, and the like.

“Alkylamino” refers to an NH or N group, the nitrogen atom of said groupbeing attached to 1 or 2 alkyl substituents, respectively, where alkylis as defined above. The alkylamino is bound through the nitrogen atomof the group. In one embodiment, alkylamino refers to a (alkyl)NH

group. In another embodiment, alkylamino refers to a (alkyl)(alkyl)N

group, i.e., a “dialkylamino”. When the nitrogen atom is bound to 2alkyls, each alkyl group may be independently selected. In anotherembodiment, two alkyl groups on the nitrogen atom may be taken togetherwith the nitrogen to which they are attached to form a 3- to 7-memberednitrogen-containing heterocycle wherein up to two of the carbon atoms ofthe heterocycle can be replaced with N(H), N(C to C₆ alkyl), N(aryl),N(heteroaryl), O, S, S(O), or S(O)₂. Examples of alkylamino include, butare not limited to CH₃NH, CH₃CH₂NH, CH₃CH₂CH₂NH, CH₃CH₂CH₂CH₂NH,(CH₃)₂CHNH, (CH₃)₂CHCH₂NH, CH₃CH₂CH(CH₃)NH, (CH₃)₃CNH, N(CH₃)₂,N(CH₂CH₃)(CH₃), N(CH₂CH₃)₂, N(CH₂CH₂CH₃)₂, N(CH₂CH₂CH₂CH₃)₂,N(CH(CH₃)₂)(CH₃), and the like.

“Aminoalkyl” refers to an alkyl group having an NH₂ substituent. Theaminoalkyl is bound through one carbon atom of the group. That is,alkylamino refers to a NH₂(alkyl)

group. Examples of aminoalkyl include, but are not limited to CH₂NH₂,CH₂CH₂NH₂, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂CH₂NH₂, C(CH₃)₂NH₂, C(CH₃)₂CH₂NH₂, andthe like.

“Alkylcarbonylamino” refers to an (alkyl)C(O)NH

group, which is bound through the nitrogen atom. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylcarbonylamino include, but are not limited to, CH₃CONH, CH₃CH₂CONH,CH₃CH₂CH₂CONH, CH₃CH(CH₃)CONH, and the like.

“Alkylsulfonylamino” refers to an (alkyl)SO₂NH

group which is bound through the nitrogen atom. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylsulfonylamino include, but are not limited to CH₃SO₂NH,CH₃CH₂SO₂NH, CH₃CH₂CH₂SO₂NH, CH₃CH(CH₃)SO₂NH, and the like.

“Alkylaminocarbonyl” refers to an (alkyl)NHC(O)

group, which is bound through the carbonyl moiety. The alkyl group isdefined and optionally substituted as described above. Examples ofalkylaminocarbonyl include, but are not limited to, CH₃NHCO, CH₃CH₂NHCO,CH₃CH₂CH₂NHCO, CH₃CH(CH₃)NHCO, and the like.

A “patient” or “subject” is a mammal, e.g., a human or a veterinarypatient or subject, e.g., mouse, rat, guinea pig, dog, cat, horse, cow,pig, or non-human primate, such as a monkey, chimpanzee, baboon orgorilla.

The term “treating” or “treatment” is meant to encompass administeringto a subject a compound of the present invention for the purposes ofamelioration of one or more symptoms of a disease or disorder, includingpalliative care. A “therapeutically effective amount” refers to theminimum amount of the active compound which effects treatment.

The following abbreviations are used herein and have the indicateddefinitions: ACN is acetonitrile; conc. is concentrated; DMSO isdimethylsulfoxide; DCM is dichloromethane; DIPEA isdiisopropylethylamine; DMF is N,N-dimethylformamide; dppf is1,1′-bis(diphenylphosphino)ferrocene; EDTA is ethylenediaminetetraacetic acid; EGTA is ethylene glycol tetraacetic acid; ELISA isenzyme-linked immunosorbent assay; ESI is electrospray ionization; E1 iselectron impact ionization; HEPES is(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HPLC is highperformance liquid chromatography; Hz is hertz; KOAc is potassiumacetate; LC is liquid chromatography; MS is mass spectroscopy; MeOH ismethanol; MHz is megahertz; mM is millimolar; mL is milliliter; min isminutes; mol is moles; M⁺ is molecular ion; [M+H]⁺ is protonatedmolecular ion; N is normality; NMR is nuclear magnetic resonance; PIP2is 5-bisphosphate; PBS is phosphate buffered saline; PH is pleckstrinhomology; PPh₃ is triphenylphosphine; psi is pound per square inch; PPMis parts per million; rt is room temperature; TLC is thin layerchromatography; TEA is triethylamine; THF is tetrahydrofuran; and XTT issodium2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazoliuminner salt.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The words “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein, the term “about” means a variability of 10% from thereference given, unless otherwise specified.

Methods useful for making the compounds of formula (I) are set forth inthe Examples below and generalized in Schemes 1-16. One of skill in theart will recognize that Schemes 1-16 can be adapted to produce the othercompounds of formula (I) and pharmaceutically acceptable salts ofcompounds of formula (I) according to the present invention.

The following methods outline the synthesis of the compounds of formula(I). The following examples are presented to illustrate certainembodiments of the present invention, but should not be construed aslimiting the scope of this invention.

Scheme 1 depicts the synthesis of boronic acid pinacol esterintermediate [1A]. In one embodiment, a bromo substituted benzoic acid[A1] is converted to the corresponding aniline [B1]. In one embodiment,the benzoic acid is reacted with diphenylphosphoryl azide (DPPA). Theaniline may then be converted to corresponding sulfonamide [C1]. In oneembodiment, the aniline is reacted with a sulfonyl chloride. In anotherembodiment, the reaction is performed in the presence of a base such aspyridine. The intermediate boronic acid pinacol ester [1A] may then beformed by reacting the sulfonamide with a diboron reagent. In oneembodiment, the sulfonamide is reacted with bis(pinacolato)diboron.

Scheme 1A depicts the synthesis of boronic acid pinacol esterintermediate [1]. 3-Bromo-2-fluoro benzoic acid is converted into thecorresponding aniline [B] using DPPA. The aniline is then converted tocorresponding sulfonamide using a sulfonyl chloride and pyridine indichloromethane. The intermediate boronic acid pinacol ester [1] wasformed by reacting the sulfonamide with bis(pinacolato)diboron.

Scheme 2 provides the second route for the preparation of intermediate[1A]. In this route, alcohol R⁷OH [D] was reacted a sulfonyl chlorideprovide sulfonate ester [E]. The sulfonate ester [E] was then convertedto the corresponding ethanethioate [F]. In one embodiment, the reactionwas performed using potassium thioacetate. This ethanethioate [F] wasthen oxidized to R⁷SO₂Cl [G]. In one embodiment, the oxidation wasperformed using chlorine gas. The transformation to sulfonamide [C1] wasachieved using aniline [B] (described in Scheme 1). The intermediateboronic acid pinacol ester [1A] was formed as described in Scheme 1.

Scheme 2A provides the second route for the preparation of intermediate[1]. In this route, alcohol R⁷OH [D] was reacted a sulfonyl chlorideprovide a sulfonate ester. The sulfonate ester [E] was then converted tothe corresponding ethanethioate [F]. In one embodiment, this reactionwas performed using potassium thioacetate. This ethanethioate [F] wasthen oxidized to R³SO₂Cl. In one embodiment, the oxidation was performedusing chlorine gas. The transformation to the sulfonamide [C] wasachieved using aniline [B] (described in Scheme 1). In one embodiment,the reaction was performed in the presence of a base such as pyridineand DMAP. The intermediate boronic acid pinacol ester [1] as formed asdescribed in Scheme 1A.

Scheme 3 depicts the synthesis of boronic acid pinacol esterintermediate [2A]. Substituted bromobenzene [H1] is converted to thecorresponding nitro compound [J1]. In one embodiment, the nitro compoundis preparing using a nitric acid in sulfuric acid. The nitro compound isthen reduced to the corresponding aniline [K1]. In one embodiment, thereduction is performed using SnCl₂.2H₂O. Aniline [K1] is then convertedto the corresponding sulfonamide intermediate [2A] using R⁷SO₂Cl asdescribed in Scheme 1. In one embodiment, the reaction is performed in abase such as DMAP and pyridine.

Scheme 3A depicts the synthesis of boronic acid pinacol esterintermediate [2]. Substituted bromofluoro benzene [H] is converted tothe corresponding nitro compound [J] using a nitration mixture insulfuric acid. Nitro compound [J] is then reduced to the correspondinganiline [K] using SnCl₂.2H₂O. The aniline is then converted intocorresponding sulfonamide intermediate [2] using R⁷SO₂Cl, DMAP andpyridine.

Scheme 4 provides a method for the synthesis of boronic acid pinacolester intermediate [3]. In this route, 4-bromophenylisocyanate [SSS] wasreacted with R⁹NH₂ to form the corresponding urea [L]. Intermediateboronic acid pinacole ester [3] was then formed by reacting urea [L]with bis(pinacolato)diboron.

Scheme 5A provides the preparation of intermediate [4A]. Specifically,compound [M1] was reacted with phenylchloroformate in the presence ofdiisopropylethylamine. The resultant compound [N1] was heated toelevated temperatures in a sealed tube. Urea compound [01] was thenreacted with bis(pinacolato)diboron to provide intermediate compound[4A].

Scheme 5A provides the preparation of intermediate [4]. Specifically,5-bromopyridin-2-amine was reacted with phenylchloroformate in thepresence of diisopropylethylamine. The resultantphenyl(5-bromopyridin-2-yl)carbamate, methylamine was heated to elevatedtemperatures in a sealed tube. 1-(5-Bromopyridin-2-yl)-3-methylurea wasthen reacted with bis(pinacolato)diboron to provide intermediatecompound [4].

Scheme 6 depicts the synthesis of boronic acid pinacol esterintermediate [5A]. In one embodiment, compound [P1] was brominated tothe 5-bromo compound [Q1]. In one embodiment, the bromination wasperformed using N-bromosuccinimide. The 5-bromo compound [Q1] was thenconverted into the corresponding boronic acid pinacol ester intermediate[5A]. In one embodiment, the reaction was performed usingbis(pinacolato)diboron.

Scheme 6A depicts the synthesis of boronic acid pinacol esterintermediate [5]. In one embodiment, compound [P] was brominated to the5-bromo compound [Q]. In one embodiment, the bromination was performedusing N-bromosuccinimide. The 5-bromo compound [Q] was then convertedinto the corresponding boronic acid pinacol ester intermediate [5]. Inone embodiment, the reaction was performed using bis(pinacolato)diboron.

Scheme 6B depicts the synthesis of boronic acid pinacol esterintermediate [5B]. In one embodiment, compound [P2] was brominated tothe 5-bromo compound [Q2]. In one embodiment, the bromination wasperformed using N-bromosuccinimide. The 5-bromo compound [Q2] was thenconverted into the corresponding boronic acid pinacol ester intermediate[5B]. In one embodiment, the reaction was performed usingbis(pinacolato)diboron.

Scheme 7 provides the route for the preparation of intermediate [6A]. Inthis route, 3-fluoro bromobenzene was converted into the correspondingformyl compound [S]. In one embodiment, the conversion was performedusing diisopropylamine and n-butyllithium. Formyl compound [S] was thenreacted with hydrazinehydrate to form bromoindazole [T]. Compound [T] isthen R¹⁶-protected. In one embodiment, the protection was performedusing 3,4-dihydro-2H-pyran. The intermediate boronic acid pinacol ester[6A] was then formed by reacting compound [U1] withbis(pinacolato)diboron.

Scheme 7A provides the route for the preparation of intermediate [6]. Inthis route, 3-fluoro bromobenzene was converted into the correspondingformyl compound [S]. In one embodiment, the conversion was performedusing diisopropylamine and n-butyllithium. Formyl compound [S] was thenreacted with hydrazine hydrate to form bromoindazole [T]. Compound [T]was protected with tetrahydropyran using 3,4-dihydro-2H-pyran. Theintermediate boronic acid pinacol ester [6] was then formed by reactingcompound [U] with bis(pinacolato)diboron.

Scheme 8 details the preparation of difluromethylbenzimidazoleintermediate [7]. In this route, o-phenylenediamine [V] was converted todifluoromethylbenzimidazole intermediate [7] using difluoroacetic acid.

Scheme 9 provides the synthesis of compounds which are encompassed byformula (I). Specifically, compound [X1] was converted to compound [Yl]using a strong base. In one embodiment, the strong base is potassiumhydroxide. Compound [Yl] was then R¹-substituted. In one embodiment, theR¹-substitution was performed using an alkylating agent. Resultantcompound [Z1] was then reduced to the corresponding aniline [AA1].Compound [AA1] was then brominated to form the corresponding bromocompound [BB1]. In one embodiment, the bromination was performed usingbromine. Bromo compound [BB1] was then converted to the correspondingquinazolinedione [CC1] using urea. The quinazolinedione was thenchlorinated at 2^(nd) and 4^(th) positions to provide compound [DD1]. Inone embodiment, the chlorination was performed using a chlorinatingagent such as POCl₃. The 4^(th) position of quinazoline [DD1] was thensubstituted by reaction with morpholine. The 6^(th) position ofquinazoline compound [E1] was then coupled with intermediate [1A].Finally, the title compound was R⁶-substituted. In one embodiment, thereaction was performed using any one of intermediates [3], [4A], [5A],[5B] or [6A].

Scheme 9A provides the synthesis of compounds which are encompassed bythe structural formula (I). Specifically, 3-chloro-2-nitrobenzoic acid[X] was converted to the corresponding 3-hydroxy-2-nitrobenzoic acid [Y]using a strong base such potassium hydroxide. The resultant acid wasthen alkylated with an alkylating agent such as methyl iodide. Theresulting dimethyl compound [Z] was then reduced to the correspondinganiline [AA]. In one embodiment, the reduction was performed using Pd/Cand hydrogen gas. The aniline was then brominated to form thecorresponding bromo compound [BB]. In one embodiment, the brominationwas performed using bromine. The bromo compound [BB] was then convertedto the corresponding quinazolinedione [CC] using urea. Thequinazolinedione was then chlorinated at 2^(nd) and 4^(th) positions. Inone embodiment, the chlorination was performed using a chlorinatingagent such as POCl₃. The 4^(th) position of quinazoline [DD] was thensubstituted by reaction with morpholine. The 6^(th) position ofquinazoline [EE] was then coupled with intermediate [1]. Finally, thetitle compound was formed by reacting the compound [FF] withintermediate [3], [4], [5], or [6].

Scheme 10 provides the synthesis of compounds which are encompassed byformula (I). In this scheme, compound [GG2] was converted to phenolcompound [HH2]. In one embodiment, the reaction was performed usingboron tribromide. Phenol compound [HH2] was then R¹-substituted at theOH group. In one embodiment, the substitution was performed using anR¹-alkyl halide. The 6^(th) position of compound [II2] was thensubstituted to form compound [JJ2]. Finally, the title compound wasformed by R⁶-substituting compound [JJ2].

Scheme 10A provides the synthesis of compounds which are encompassed byformula (I). In this scheme, compound [GG1] was converted to phenolcompound [HH1]. In one embodiment, the reaction is performed using borontribromide. Phenol compound [HH1] was then R¹-substituted at the OHgroup. In one embodiment, the alkylation was performed using an R¹-alkylhalide. The 6^(th) position of compound [II1] was then coupled withintermediate [1] (described in Scheme 1A) to form compound [JJ1].Finally, the title compound was formed by reacting compound [JJ1] withintermediate [5A].

Scheme 10B provides the synthesis of compounds which are encompassed byformula (I). In this scheme, compound [GG] was converted to phenolcompound [HH]. In one embodiment, the reaction is performed using borontribromide. Phenol compound [HH] was then converted to compound [II]using an R¹-alkyl halide. The 6^(th) position of compound [II] was thencoupled with intermediate [1] to form compound [JJ]. Finally, the titlecompound was formed by reacting compound [JJ] with intermediate [5B].

Scheme 11 provides the synthesis of compounds which are encompassed byformula (I). Specifically, the chloro group in compound [X1] wasreplaced with a NR²R³ group. In one embodiment, the reaction wasperformed using NHR²R³. In another embodiment, the reaction wasperformed using morpholine. The acid group of compound [KK2] was thenalkylated to form the alkyl ester. In one embodiment, the alkylation wasperformed using methyl iodide. Methyl ester [LL2] was then reduced toaniline [MM2]. In one embodiment, the reduction was performed using Pd/Cand hydrogen gas. The aniline compound [MM2] was then brominated to formbromo compound [NN2]. In one embodiment, the bromination was performedusing bromine. Bromo compound [NN2] was then converted toquinazolinedione [OO2] using urea. Quinazolinedione [OO2] was thenchlorinated at the 2^(nd) and 4^(th) positions to form compound [PP2].In one embodiment, the chlorination was performed using POCl₃. The4^(th) position of quinazoline [PP2] was then substituted by reactionwith an optionally substituted morpholine (R⁴) to afford compound [QQ2].The 6^(th) position of compound [QQ2] was then substituted to formcompound [RR2]. Finally, the title compound was formed byR⁶-substituting compound [RR2].

Scheme 11A provides the synthesis of compounds which are encompassed byformula (I). Specifically, the chloro group in compound [X] was replacedwith a NR²R³ group. In one embodiment, the reaction was performed usingNHR²R³. In another embodiment, the reaction was performed usingmorpholine. The acid group of compound [KK1] was then alkylated to formalkyl ester [LL1]. In one embodiment, the alkylation was performed usingmethyl iodide. The methyl ester was then reduced to aniline [MM1]. Inone embodiment, the reduction was performed using Pd/C and hydrogen gas.The aniline compound [MM1] was then brominated to form bromo compound[NN1]. In one embodiment, the bromination was performed using bromine.Bromo compound [NN1] was then converted to quinazolinedione [OO1] usingurea. Quinazolinedione [OO1] was then chlorinated at the 2^(nd) and4^(th) positions to form compound [PP1]. In one embodiment, thechlorination was performed using POCl₃. The 4^(th) position ofquinazoline [PP1] was then substituted by reaction with an optionallysubstituted morpholine (R⁴) to afford compound [QQ1]. The 6^(th)position of compound [QQ1] was then coupled with intermediate [1] toform compound [RR1]. Finally, the title compound was formed by reactingcompound [RR1] with intermediate [5A].

Scheme 11B provides the synthesis of compounds which are encompassed byformula (I). Specifically, 3-chloro-2-nitrobenzoic acid [X] wasconverted to the corresponding 3-morpholino compound [KK] usingmorpholine. The morpholine compound [KK] was then alkylated with methyliodide to form methyl ester [LL]. The methyl ester was then reduced toaniline [MM]. In one embodiment, the reduction was performed using Pd/Cand hydrogen gas. The aniline compound [MM] was then brominated to formbromo compound [NN]. In one embodiment, the bromination was performedusing bromine. Bromo compound [NN] was then converted toquinazolinedione [OO] using urea. Quinazolinedione [OO] was thenchlorinated at the 2^(nd) and 4^(th) positions to form compound [PP]. Inone embodiment, the chlorination was performed using POCl₃. The 4^(th)position of quinazoline [PP] was then substituted by reaction withmorpholine to afford compound [QQ]. The 6^(th) position of compound [QQ]was then coupled with intermediate [1] to form compound [RR]. Finally,the title compound was formed by reacting compound [RR] withintermediate [5A].

Scheme 12 provides the synthesis of compounds which encompassed byformula (I). Specifically, compound [EE2] was converted to thecorresponding boronic acid pinacol ester [SS2] usingbis(pinacolato)diboron. Boronic acid pinacol ester [SS2] was thensubstituted to afford compound [TT1]. Finally, R⁶-substitution ofcompound [TT1] provided the title product.

Scheme 12A provides the synthesis of compounds which encompassed byformula (I). Specifically, compound [EE3] was converted to thecorresponding boronic acid pinacol ester [SS1] usingbis(pinacolato)diboron. Boronic acid pinacol ester [SS1] was thencoupled with intermediate [2] to afford compound [TT1]. Finally,reaction of compound [TT1] with intermediate [5A] provided the titleproduct.

Scheme 12B provides the synthesis of compounds which encompassed byformula (I). In this scheme, morpholine compound [EE] was converted tothe corresponding boronic acid pinacol ester [SS] usingbis(pinacolato)diboron. Boronic acid pinacol ester [SS] was then coupledwith intermediate [2] to afford compound [TT]. Finally, reaction ofcompound [TT] with intermediate [5] provided the title product.

Scheme 13 provides the synthesis of compounds encompassed by formula(I). Specifically, compound [UU2] was converted to compound [VV2] usingCuCN. The cyano compound was then reduced to afford compound [WW2]. Inone embodiment, the reduction was performed using stannous chloridedehydrate. Compound [WW2] was cyclized to compound [XX2]. In oneembodiment, the cyclization was performed using triphosgene. Compound[XX2] was then chlorinated at 2^(nd) and 4^(th) positions to form thecorresponding trichloro compound [YY2]. In one embodiment, thechlorination was performed using a chlorinating agent such as POCl₃. The4^(th) position of compound [YY2] was then R⁴-substituted. In oneembodiment, the R⁴-substitution was performed using morpholine. The6^(th) position of compound [ZZ2] was then substituted to form compound[AAA2]. Finally, the title compound was formed by R⁶-substitutingcompound [AAA2].

Scheme 13A provides the synthesis of compounds encompassed by formula(I). Specifically, compound [UU] was converted to compound [VV1] usingCuCN. Cyano compound [VV1] was then reduced to afford compound [WW1]. Inone embodiment, the reduction was performed using stannous chloridedehydrate. The picolinamide compound [WW1] was cyclized to5-azaquinazolinedione [XX1]. In one embodiment, the cyclization wasperformed using triphosgene. Compound [XX1] was then chlorinated at2^(nd) and 4^(th) positions to form the corresponding trichloro compound[YY1] using a chlorinating agent such as POCl₃. The 4^(th) position ofthe azaquinazoline [YY1] was then R⁴-substituted. The 6^(th) position ofthe resultant compound [ZZ1] was then coupled with intermediate [1] toform compound [AAA1]. Finally, the title compound was formed by reactingcompound [AAA1] with intermediate [5A] or [6].

Scheme 13B provides the synthesis of compounds encompassed by formula(I). Specifically, 2,6-dichloro 3-nitropyridine [UU] was converted into6-chloro-3-nitropicolinonitrile [VV] using CuCN. Cyano compound [VV] wasthen reduced to afford 3-amino-6-chloropicolinamide [WW]. In oneembodiment, the reduction was performed using stannous chloridedehydrate. The picolinamide compound [WW] was cyclized to5-azaquinazolinedione [XX]. In one embodiment, the cyclization wasperformed using triphosgene. 5-Azaquinazolinedione [XX] was thenchlorinated at 2^(nd) and 4^(th) positions to form the correspondingtrichloro compound [YY] using a chlorinating agent such as POCl₃. The4^(th) position of the azaquinazoline [YY] was then substituted withmorpholine using morpholine. The 6^(th) position of the resultantcompound [ZZ] was then coupled with intermediate [1] to form compound[AAA]. Finally, the title compound was formed by reacting compound [AAA]with intermediate [5B] or [6].

Scheme 14 provides the synthesis of compounds encompassed by formula(I). Specifically, compound [BBB1] was converted into the correspondinghydroxyimino [CCC1]. In one embodiment, this reaction was performedusing chloral hydrate and NH₂OH.HCl. Reaction of hydroxyimino compound[CCC1] with a strong acid resulted in the preparation of cyclic isatin[DDD1]. In one embodiment, the strong acid was H₂SO₄. Isatin compound[DDD1] was brominated to afford compound [EEE1]. In one embodiment, thebromination was performed using bromine. The isatin ring of bromocompound [EEE1] was then cleaved. In one embodiment, this reaction wasperformed using aqueous H₂O₂ and NaOH. The resultant amino benzoic acid[FFF1] was converted to quinazoline dione [GGG1] using urea.Quinazolinedione [GGG1] was then chlorinated at 2^(nd) and 4^(th)positions to form compound [HHH1]. In one embodiment, the chlorinationwas performed using POCl₃. The 4 position of quinazoline [HHH1] was thenR⁴-substituted to afford compound [III1]. The 6^(th) position ofcompound [III1] was substituted to form compound [JJJ1]. Finally, thetitle compound was formed by R⁶-substituting compound [JJJ1].

Scheme 14A provides the synthesis of compounds encompassed by formula(I). Specifically, compound [BBB] was converted into the correspondinghydroxyimino [CCC] using chloral hydrate and NH₂OH.HCl. Reaction ofhydroxyimino compound [CCC] with a strong acid resulted in thepreparation of cyclic isatin [DDD]. In one embodiment, the strong acidwas H₂SO₄. Isatin compound [DDD] was brominated to afford compound[EEE]. In one embodiment, the bromination was performed using bromine.The isatin ring of bromo compound [EEE] was then cleaved using aqueousH₂O₂ and NaOH. The resultant amino benzoic acid [FFF] was converted intoquinazoline dione [GGG] using urea. Quinazolinedione [GGG] was thenchlorinated at 2^(nd) and 4^(th) positions to form compound [HHH] usinga chlorinating agent such as POCl₃. The 4^(th) position of quinazoline[III] was then R⁴-substituted to afford compound [III]. The 6^(th)position of compound [III] was then coupled with intermediate [1] toform compound [JJJ] using. Finally, the title compound was formed byreacting compound [JJJ] with intermediate [5A] or [6].

Scheme 15 provides the synthesis of compounds encompassed by formula(I). Specifically, compound [EE4] was coupled with intermediate [7] or[8] to form compound [JJJ]. Finally, the title compound was formed byreacting compound [JJJ1] with intermediate [1].

Scheme 15A provides the synthesis of compounds encompassed by formula(I). Specifically, compound [EE] was coupled with intermediate [7] or[8] to form compound [JJJ2]. Finally, the title compound was formed byreacting compound [JJJ2] with intermediate [1].

Scheme 16 provides the synthesis of compounds which are encompassed byformula (I). Specifically, compound [KKK] was brominated to form bromocompound [LLL]. In one embodiment, the bromination was performed usingbromine. Bromo compound [LLL] was then methylated to form methyl ester[MMM]. In one embodiment, the methylation was performed using methyliodide. Methyl ester [MMM] was then converted to urea compound [NNN] byreaction with potassium cyanate. Urea compound [NNN] was then convertedto quinazolinedione [OO0] by treatment with a strong base. In oneembodiment, the strong base is sodium hydroxide. Quinazolinedione [OO0]was then chlorinated at the 2¹ and 4^(th) positions to form compound[PPP]. In one embodiment, the chlorination was performed using POCl₃.The 4^(th) position of quinazoline [PPP] was then substituted byreaction with an optionally substituted morpholine (R⁴) to affordcompound [QQQ]. The 6^(th) position of compound [QQQ] was thensubstituted to form compound [RRR]. Finally, the title compounds wereformed by R⁶-substituting compound [RRR].

Pharmaceutical compositions useful herein contain a compound of formula(I) in a pharmaceutically acceptable carrier optionally with otherpharmaceutically inert or inactive ingredients. In another embodiment, acompound of formula (I) is present in a single composition. In a furtherembodiment, a compound of formula (I) is combined with one or moreexcipients and/or other therapeutic agents as described below.

The pharmaceutical compositions of the invention comprise an amount of acompound of formula (I) or a pharmaceutically acceptable salt thereofthat is effective for regulating one or both of the RAS/RAF/MEK/ERK andPI3K/AKT/PTEN/mTOR pathways in a subject. Specifically, the dosage ofthe compound of formula (I) to achieve a therapeutic effect will dependon the formulation, age, weight and sex of the patient and route ofdelivery. It is also contemplated that the treatment and dosage of thecompound of formula (I) may be administered in unit dosage form and thatone skilled in the art would adjust the unit dosage form accordingly toreflect the relative level of activity. The decision as to theparticular dosage to be employed (and the number of times to beadministered per day) is within the discretion of the ordinarily-skilledphysician, and may be varied by titration of the dosage to theparticular circumstances to produce the desired therapeutic effect. Inone embodiment, the therapeutically effective amount is about 0.01 mg/kgto 10 mg/kg body weight. In another embodiment, the therapeuticallyeffective amount is less than about 5 g/kg, about 500 mg/kg, about 400mg/kg, about 300 mg/kg, about 200 mg/kg, about 100 mg/kg, about 50mg/kg, about 25 mg/kg, about 10 mg/kg, about 1 mg/kg, about 0.5 mg/kg,about 0.25 mg/kg, about 0.1 mg/kg, about 100 μg/kg, about 75 μg/kg,about 50 μg/kg, about 25 μg/kg, about 10 μg/kg, or about 1 g/kg.However, the therapeutically effective amount of the compound of formula(I) can be determined by the attending physician and depends on thecondition treated, the compound administered, the route of delivery, theage, weight, severity of the patient's symptoms and response pattern ofthe patient.

The therapeutically effective amounts may be provided on regularschedule, i.e., daily, weekly, monthly, or yearly basis or on anirregular schedule with varying administration days, weeks, months, etc.Alternatively, the therapeutically effective amount to be administeredmay vary. In one embodiment, the therapeutically effective amount forthe first dose is higher than the therapeutically effective amount forone or more of the subsequent doses. In another embodiment, thetherapeutically effective amount for the first dose is lower than thetherapeutically effective amount for one or more of the subsequentdoses. Equivalent dosages may be administered over various time periodsincluding, but not limited to, about every 2 hours, about every 6 hours,about every 8 hours, about every 12 hours, about every 24 hours, aboutevery 36 hours, about every 48 hours, about every 72 hours, about everyweek, about every two weeks, about every three weeks, about every month,and about every two months. The number and frequency of dosagescorresponding to a completed course of therapy will be determinedaccording to the judgment of a health-care practitioner. Thetherapeutically effective amounts described herein refer to totalamounts administered for a given time period; that is, if more than onecompound of formula (I) or a pharmaceutically acceptable salt thereof isadministered, the therapeutically effective amounts correspond to thetotal amount administered.

The pharmaceutical compositions containing a compound of formula (I) maybe formulated neat or with one or more pharmaceutical carriers foradministration. The amount of the pharmaceutical carrier(s) isdetermined by the solubility and chemical nature of the compound offormula (I), chosen route of administration and standard pharmacologicalpractice. The pharmaceutical carrier(s) may be solid or liquid and mayincorporate both solid and liquid carriers. A variety of suitable liquidcarriers is known and may be readily selected by one of skill in theart. Such carriers may include, e.g., DMSO, saline, buffered saline,hydroxypropylcyclodextrin, and mixtures thereof. Similarly, a variety ofsolid carriers and excipients are known to those of skill in the art.The compounds of formula (I) may be administered by any route, takinginto consideration the specific condition for which it has beenselected. The compounds of formula (I) may, be delivered orally, byinjection, inhalation (including orally, intranasally andintratracheally), ocularly, transdermally, intravascularly,subcutaneously, intramuscularly, sublingually, intracranially,epidurally, rectally, and vaginally, among others.

Although the compound of formula (I) may be administered alone, it mayalso be administered in the presence of one or more pharmaceuticalcarriers that are physiologically compatible. The carriers may be in dryor liquid form and must be pharmaceutically acceptable. Liquidpharmaceutical compositions are typically sterile solutions orsuspensions. When liquid carriers are utilized for parenteraladministration, they are desirably sterile liquids. Liquid carriers aretypically utilized in preparing solutions, suspensions, emulsions,syrups and elixirs. In one embodiment, the compound of formula (I) isdissolved a liquid carrier. In another embodiment, the compound offormula (I) is suspended in a liquid carrier. One of skill in the art offormulations would be able to select a suitable liquid carrier,depending on the route of administration. The compound of formula (I)may alternatively be formulated in a solid carrier. In one embodiment,the composition may be compacted into a unit dose form, i.e., tablet orcaplet. In another embodiment, the composition may be added to unit doseform, i.e., a capsule. In a further embodiment, the composition may beformulated for administration as a powder. The solid carrier may performa variety of functions, i.e., may perform the functions of two or moreof the excipients described below. For example, solid carrier may alsoact as a flavoring agent, lubricant, solubilizer, suspending agent,filler, glidant, compression aid, binder, disintegrant, or encapsulatingmaterial.

The composition may also be sub-divided to contain appropriatequantities of the compound of formula (I). For example, the unit dosagecan be packaged compositions, e.g., packeted powders, vials, ampoules,prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more compoundof formula (I) include, without limitation, adjuvants, antioxidants,binders, buffers, coatings, coloring agents, compression aids, diluents,disintegrants, emulsifiers, emollients, encapsulating materials,fillers, flavoring agents, glidants, granulating agents, lubricants,metal chelators, osmo-regulators, pH adjustors, preservatives,solubilizers, sorbents, stabilizers, sweeteners, surfactants, suspendingagents, syrups, thickening agents, or viscosity regulators. See, forexample, the excipients described in the “Handbook of PharmaceuticalExcipients”, 5^(th) Edition, Eds.: Rowe, Sheskey, and Owen, APhAPublications (Washington, D.C.), Dec. 14, 2005, which is incorporatedherein by reference.

In one embodiment, the compositions may be utilized as inhalants. Forthis route of administration, compositions may be prepared as fluid unitdoses using a compound of formula (I) and a vehicle for delivery by anatomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols,i.e., oral or intranasal. For this route of administration, thecompositions are formulated for use in a pressurized aerosol containertogether with a gaseous or liquefied propellant, e.g.,dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and thelike. Also provided is the delivery of a metered dose in one or moreactuations.

In another embodiment, the compositions may be administered by asustained delivery device. “Sustained delivery” as used herein refers todelivery of a compound of formula (I) which is delayed or otherwisecontrolled. Those of skill in the art know suitable sustained deliverydevices. For use in such sustained delivery devices, the compound offormula (I) is formulated as described herein.

In addition to the components described above for use in the compositionand the compound of formula (I), the compositions and kits describedherein may contain one or more medications or therapeutic agents whichare used to treat cancers, including, e.g., cancers characterized bytumors, including solid tumors, and “liquid” or non-solid tumor cancers(e.g., lymphoma). In one embodiment, the medication is achemotherapeutic. Examples of chemotherapeutics include those recited inthe “Physician's Desk Reference”, 64^(th) Edition, Thomson Reuters,2010, which is hereby incorporated by reference. Therapeuticallyeffective amounts of the additional medication(s) or therapeutic agentsare well known to those skilled in the art. However, it is well withinthe attending physician to determine the amount of other medication tobe delivered.

The compounds of formula (I) and/or other medication(s) or therapeuticagent(s) may be administered in a single composition. However, thepresent invention is not so limited. In other embodiments, the compoundsof formula (I) may be administered in one or more separate formulationsfrom other compounds of formula (I), chemotherapeutic agents, or otheragents as is desired.

Also provided herein are kits or packages of pharmaceutical formulationscontaining the compounds of formula (I) or compositions describedherein. The kits may be organized to indicate a single formulation orcombination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound offormula (I) formulated for the desired delivery route. Suitably, the kitcontains instructions on dosing and an insert regarding the activeagent. Optionally, the kit may further contain instructions formonitoring circulating levels of product and materials for performingsuch assays including, e.g., reagents, well plates, containers, markersor labels, and the like. Such kits are readily packaged in a mannersuitable for treatment of a desired indication. For example, the kit mayalso contain instructions for use of a spray pump or other deliverydevice. Other suitable components to include in such kits will bereadily apparent to one of skill in the art, taking into considerationthe desired indication and the delivery route.

The compounds of formula (I) or compositions described herein can be asingle dose or for continuous or periodic discontinuous administration.For continuous administration, a package or kit can include the compoundof formula (I) in each dosage unit (e.g., solution, lotion, tablet,pill, or other unit described above or utilized in drug delivery), andoptionally instructions for administering the doses daily, weekly, ormonthly, for a predetermined length of time or as prescribed. When thecompound of formula (I) is to be delivered periodically in adiscontinuous fashion, a package or kit can include placebos duringperiods when the compound of formula (I) is not delivered. When varyingconcentrations of a composition, of the components of the composition,or the relative ratios of the compounds of formula (I) or agents withina composition over time is desired, a package or kit may contain asequence of dosage units which provide the desired variability.

A number of packages or kits are known in the art for dispensingpharmaceutical agents for periodic oral use. In one embodiment, thepackage has indicators for each period. In another embodiment, thepackage is a labeled blister package, dial dispenser package, or bottle.

The packaging means of a kit may itself be geared for administration,such as an inhalant, syringe, pipette, eye dropper, or other suchapparatus, from which the formulation may be applied to an affected areaof the body, such as the lungs, injected into a subject, or even appliedto and mixed with the other components of the kit.

The compositions of these kits also may be provided in dried orlyophilized forms. When reagents or components are provided as a driedform, reconstitution generally is by the addition of a suitable solvent.It is envisioned that the solvent also may be provided in anotherpackage.

The kits of the present invention also will typically include a meansfor containing the vials in close confinement for commercial sale suchas, e.g., injection or blow-molded plastic containers into which thedesired vials are retained. Irrespective of the number or type ofpackages and as discussed above, the kits also may include, or bepackaged with a separate instrument for assisting with theinjection/administration or placement of the composition within the bodyof an animal. Such an instrument may be an inhalant, syringe, pipette,forceps, measuring spoon, eye dropper or any such medically approveddelivery means.

In one embodiment, a kit is provided and contains a compound of formula(I). The compound of formula (I) may be in the presence or absence ofone or more of the carriers or excipients described above. The kit mayoptionally contain instructions for administering the medication and thecompound of formula (I) to a subject having a disease characterized bythe dysregulation of one of both of the RAS/RAF/MEK/ERK andPI3K/AKT/PTEN/mTOR pathways.

In a further embodiment, a kit is provided and contains a compound offormula (I) in a second dosage unit, and one or more of the carriers orexcipients described above in a third dosage unit. The kit mayoptionally contain instructions for administering the medication and thecompound of formula (I) to a subject having a disease characterized bythe dysregulation of one or both of the RAS/RAF/MEK/ERK andPI3K/AKT/PTEN/mTOR pathway.

The compounds described herein are useful in regulating conditions whichare associated with the one or more of the RAS/RAF/MEK/ERK andPI3K/AKT/PTEN/mTOR pathways. In one embodiment, such a disease isassociated with abnormal cellular proliferation. The term “abnormalcellular proliferation” refers to the uncontrolled growth of cells whichare naturally present in a mammalian body. In one embodiment, a diseasewhich is characterized by abnormal cellular proliferation is cancer,including, without limitation, cancer of the prostate, head, neck, eye,mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung,colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries,vagina, testicles, skin, thyroid, blood, lymph nodes, kidney, liver,intestines, pancreas, brain, central nervous system, adrenal gland, skinor a leukemia or lymphoma. In one embodiment, the disease characterizedby abnormal cellular proliferation is cancer of the prostate. In anotherembodiment, the abnormal cellular proliferation is associated with atleast one solid tumor.

In a further embodiment, the compounds of formula (I) regulate PI3Kactivity. Compounds of formula (I) have the ability to inhibit at leastone of the four isoforms of PI3K (α, β, δ, γ) or combinations thereof.

As used herein, the term “selectivity” as used in reference to activityto one or more isoform of PI3K refers to compounds which exhibitdifferent activity to the isoforms of PI3K. A compound which shows PI3Kisoform selectivity exhibits higher inhibition of one, two, or three ofthe α, β, δ, γ isoforms. In one embodiment, a compound which selectivelyregulates one, two or three of these isoforms exhibits no orsubstantially no activity against the other isoforms. For example,certain compounds may show selectivity for the α and δ PI3K isoforms.Other compounds described herein may have selectivity for PI3Kα, PI3Kβ,and PI3K δ. Still other compounds described herein may have selectivityfor PI3Kα and PI3Kβ. Yet other compounds may have selectivity for onlysingle isoform, e.g., α or δ.

Compounds associated with activity for the α isoform may be particularlywell suited for treatment of conditions associated with this PI3Kisoform, including, e.g., breast and gastric cancers, colorectal tumors,glioblastomas, and prostate cancer, and lung cancers.

In another embodiment, some of the compounds of formula (I) regulate thepathway of the PI3K-β isoform. In still a further embodiment, thecompounds of formula (I) regulate the pathway of the PI3K-δ isoform. Inyet another embodiment, the compounds of formula (I) regulate thepathway of the PI3K-γ isoform.

The ability of compounds to inhibit the PI3K-δ and PI3K-γ isoforms hasbeen described with the ability to treat acute and chronic inflammatorydisorders. See, e.g., RC Camps et al, Nat Rev Immunol., 2007, Mar. 7(3):191-201. Other inflammatory disorders have been associated morespecifically with the PI3K delta isoform, includingneutrophil-associated inflammation. Models for testing the ability ofcompounds to reduce inflammation in inflammatory arthritis are known,e.g., as described by Camps et al, Nature Med., 2005, 11, 936-943. Campset al (2005) also describes models useful in assessing the ability ofcompounds to reduce inflammation in peritonitis. Models for testing theability of compounds to reduce inflammation and/or improve healing aftermyocardial infarction are described by Siragusa et al, Circ. Res.(2010), 106, 757-768. A model for testing the ability of compounds toprevent bleomycin-induced pulmonary fibrosis is described by Wei et al,Biochem Biophys Res Comm. 2010, 397: 311-317 and Brent et al,Toxicology, 2000, 147: 1-13.

The term “regulation” or variations thereof as used herein refers to theability of a compound of formula (I) to inhibit one or more componentsof a biological pathway. In one embodiment, “regulation” refers toinhibition of mTOR activity. In another embodiment, “regulation” refersto inhibition of one or more isoforms of PI3K activity. Regulation maybe selective, as defined above. In a further embodiment, “regulation”refers to inhibition of RAS activity. In yet another embodiment,“regulation” refers to inhibition of RAF activity. In still a furtherembodiment, “regulation” refers to inhibition of MEK activity. Inanother embodiment, “regulation” refers to inhibition of ERK activity.In a further embodiment, “regulation” refers to inhibition of AKTactivity. In a further embodiment, “regulation” refers to inhibition ofS6RP or S6K activity. In a further embodiment, regulation refers toinhibition of two or more of the immediately preceding pathways. In yetanother embodiment, regulation includes inhibition of theRAS/RAF/MEK/ERK pathway. In a further embodiment, regulation includesinhibition of the PI3K/AKT/PTEN/mTOR pathway. In still anotherembodiment, regulation includes inhibition of the RAS/RAF/MEK/ERK andPI3K/AKT/PTEN/mTOR pathways.

The utility of the compounds of formula (I) can be illustrated, forexample, by their activity in the in vitro tumor cell proliferationassay described below. The compounds of formula (I) exhibit anRAS/RAF/MEK/ERK and/or PI3K/AKT/PTEN/mTOR inhibitory activity, andtherefore can be utilized in order to inhibit abnormal cell growth inwhich any one of these separate pathways plays a role. Thus, thecompounds of formula (I) are effective in the treatment of disorderswith which abnormal cell growth actions of RAS/RAF/MEK/ERK and/orPI3K/AKT/PTEN/mTOR dysregulation are associated, such as cancer. One ofskill in the art would recognize that is an established link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting. For example, the therapeutic utilityof a variety of pharmaceutical agents, e.g, taxol (Silvestrini, StemCells, 1993, 11(6):528-535), taxotere (Bissery, Anti Cancer Drugs, 1995,6(3):330) and topoisomerase inhibitors (Edelman, Cancer Chemother.Pharmacol., 1996, 37(5):385-39), have been demonstrated by using invitro tumor proliferation assays.

In one embodiment, methods for regulating the RAS/RAF/MEK/ERK and/orPI3K/AKT/PTEN/mTOR pathway are provided and include administering atherapeutically effective amount of a compound of formula (I) to apatient in need thereof.

In a further embodiment, methods for co-regulating the RAS/RAF/MEK/ERKand PI3K/AKT/PTEN/mTOR pathways are provided and include administering atherapeutically effective amount of a compound of formula (I) to apatient in need thereof.

In another desirable embodiment, methods for treating a diseasecharacterized by an abnormal cellular growth resulting from adysregulated RAS/RAF/MEK/ERK and/or PI3K/AKT/PTEN/mTOR pathway areprovided and include administering of a therapeutically effective amountof a compound of formula (I) to a patient in need thereof.

In a further desirable embodiment, methods for treating a conditiontreatable by inhibiting the RAS/RAF/MEK/ERK and/or PI3K/AKT/PTEN/mTORpathway are provided and include administering a therapeuticallyeffective amount of a compound of formula (I) to a patient in needthereof.

As described herein, a therapeutically effective amount of a compoundwhen used for the treatment of cancer is an amount which may reduce thenumber of cancer cells in fluids (e.g., blood, peripheral cells orlymphatic fluids), reduce tumor size, inhibit metastasis, inhibit tumorgrowth and/or ameliorate one or more of the symptoms of the cancer. Forcancer therapy, efficacy can be measured for example, by assessing thetime to disease progression and/or determining the response rate.

As described herein, a therapeutically effective amount of a compoundwhen used for the treatment of an inflammatory disorder is an amountwhich may delay the onset of or reduce the severity or duration of aninflammatory response, or which mitigates one or more symptoms of aninflammatory response. For treatment of an inflammatory disorder,efficacy can be measured, for example, by a reduction in physiologicsigns of inflammation (e.g., redness, swelling, heat, loss of function)or by measuring changes in the levels of cells (e.g., monocytes,macrophages and other mononuclear cells) or molecules (e.g.,pro-inflammatory cytokines) associated with inflammation.

RAS/RAF/MEK/ERK and/or PI3K/AKT/PTEN/mTOR pathways are known to bederegulated in various cancers due to specific mutations in differentmembers of each pathway. For example, in RAS/RAF/MEK/ERK pathway, RASprotein is mutated frequently at residues 12, 13 and 61 (see, e.g., Prioet al, Cancer Research (2012) 72(10): 2457-2467) while B-RAF is mutatedonly at amino acid position 600. The RAS gene mutations are easilydetected in tumor samples using the methods known in the art such asdescribed by Sarkar et al (Diagn Mol Pathol. (1995) 4(4):266-73), whileB-RAF mutations can be detected with an FDA approved kit available fromRoche (Cobas® 4800 BRAF V600 Mutation Test). In the PI3K/AKT/PTEN/mTORpathway, PI3K-alpha isozyme, PTEN and less frequently AKT are mutated ina wide variety of solid tumors. The PI3K-alpha subunit is commonlymutated at residues 542, 545 and 1047 (see, e.g., Karakas et al, BritishJ. Cancer (2006), 94:455-459). Similarly, mutations have been identifiedin PTEN tumor suppressor gene in a broad range of solid tumors. Most ofthe PTEN mutations render loss of PTEN activity through eitherframe-shift or non-sense mutations. About 3% of breast cancer tumorsexhibit mutations in AKT protein at position 17 (Yi et al, Oncotarget(2013) 4(1), 29-34).

Identifying a mammalian subject, e.g., a human patient, who will respondpositively to treatment with compounds of the invention prior toinitiation of treatment (also termed herein “predetermining orselecting”) can be accomplished by assaying a sample from a cancerpatient to detect one or more of the RAS, B-RAF, PI3K-α isozyme (oranother selected PI3K isozyme or combinations thereof as describedherein), PTEN or AKT mutations discussed above.

A suitable sample may be obtained from the body of a subject and mayinclude, e.g., tissue samples, cells, extracellular matter, circulatingcancer cells in blood or lymphatic fluid. These samples may be fromhumans or non-human mammalian animals. Tissue samples may be from anyorgan, including disease states of such organs, the blood circulatorysystem, and any circulating tumor cells. Tissue samples such as tumorbiopsies may be obtained using known procedures. Tissue specimens mayalso include xenograft tumor samples, e.g., those from animals in drugdose or toxicology studies.

For example, a patient can be tested for the presence of a B-RAFmutation and an mTOR mutation, for a B-RAF mutation and a PI3K mutation,or for a B-RAF mutation, an mTOR and a PI3K pathway mutation. Asdiscussed above, these mutations can be detected using any suitabletechnique known in the art, including fluorescence in situhybridization, PCR-based sequencing of relevant portions of a givengene, restriction fragment length polymorphism analysis, or bymonitoring expression levels of a given gene product (e.g., protein orRNA). B-RAF, mTOR and PI3K mutations can also be detected by measuringactivity of biomarkers in the RAS/RAF/MEK/ERK and/or PI3K/AKT/PTEN/mTORpathways. Thus, there is provided a method for treating a conditiontreatable by inhibiting the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTORpathways, comprising selecting a patient who has a B-RAF, PI3K and/orPTEN mutation; and administering a therapeutically effective amount ofat least one compound of formula (I).

The compounds of the invention show different profiles of inhibition forvarious target proteins in the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTORpathways. In one profile, compounds of the invention can inhibit B-RAFand mTOR. In another profile, compounds of the invention can inhibitB-RAF and one or more PI3K isoform. In another profile, compounds of theinvention can inhibit B-RAF, mTOR and one or more PI3K isoform. Theactivity of certain protein biomarkers can therefore be used to monitorthe efficacy of compounds of formula (I) once administered to a patient.For example, compounds of formula (I) which have dual activity as B-RAFand mTOR inhibitors will cause a reduced activity of pERK and pS6RP orpS6K. Combinations of biomarkers suitable for showing efficacy of thecompounds of the inventions are shown in Table 1.

TABLE 1 Activity Profile of compounds of formula (I) Combination ofbiomarkers B-RAF + mTOR inhibitor pERK and (pS6RP or pS6K) B-RAF + PI3Kinhibitor pERK and pAKT B-RAF + mTOR + pERK, (pS6RP or pS6K) and PI3Kinhibitor pAKT

Showing a reduced activity of one or a combination of these biomarkers(e.g., as shown in Table 1) can, for example, be used as a surrogate forthe efficacy of tumor growth inhibition in patients. Thus, there isprovided a method of monitoring the efficacy of compound of formula (I),or a method for treating a condition treatable by inhibiting theRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways, comprisingadministering at least one compound of formula (I) to a patient,evaluating the activity of pERK, (pS6RP or pS6K) or pAKT (for example,pAKT-5473 and/or pAKT-T308) or a combination thereof, and adjusting theamount of the compound administered until the activity of the pERK,(pS6RP or pS6K) or pAKT or a combination thereof is reduced to apredetermined activity level as compared to the activity level in anuntreated patient. For example, the activity of pERK can be reduced byby at least about 50%, at least about 55%, at least about 60%, at leastabout 65%, at least about 70%, at least about 75%, at least about 80%,at least about 85%, at least about 90%, or at least about 99%. Inanother example, the activity of pERK can be reduced by about 80% toabout 100%. The activity of (pS6RP or pS6K) or pAKT can be reduced forexample by at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 99%. In another example, the activity of (pS6RP or pS6K)or pAKT can be reduced by about 50% to about 100%. Compounds having anyone of these pERK, (pS6RP or pS6K), or pAKT activity reduction profilesand characterized by no, minimal, or lower reduction of the otherbiomarkers may be still be utilized. However, compounds which haveactivity reduction profiles in two of these biomarkers, or all three ofthese biomarkers are particularly well suited for the uses describedherein.

As used herein “pAKT activity profile” refers to the level of activationor phosphorylation of AKT (“pAKT”) compared to the level ofnon-activated or non-phosphorylated AKT in a given sample. In oneexample, the sample is a solid tumor cell or tissue. In another example,the sample is a non-solid tumor cancer cell or tissue. The pAKT activityprofile can be expressed in terms of a ratio (e.g., amount of pAKT in acancer cell treated with a compound of formula (I) divided by amount ofphosphorylated AKT in a cancer cell of the same type that was nottreated with a compound of formula (I)). In a typical measurement ofpAKT activity profiles, each treatment or patient sample and theuntreated control samples are normalized against total AKT (i.e.,phosphorylated AKT plus non-phosphorylated AKT) in the same sample. Thenormalized amount of pAKT in each treatment or patient sample is thendivided by the amount of pAKT in the untreated control sample, and thisnumber is multiplied by 100 to obtain the percent remaining in pAKTactivity for a given sample. The percent remaining can then besubtracted from 100 to give the percent reduction in pAKT activity. ThepAKT activity profile may also be expressed in terms of the level ofactivation of the pathway by measuring amounts of phosphorylateddownstream targets of AKT. A “reduced pAKT activity profile” refers toactivation or phosphorylation levels of overall AKT in a sample that arelower than a baseline value. Such a baseline value may be determinedbased on the basal levels of a single cell type. Alternatively, abaseline value may be based on the average or mean level of pAKT in agiven population of sample cells. In one example, for a pAKT activityprofile as used herein refers to an average value based on the pAKTactivity profile of tumor cells from patients which are untreated with acompound of the invention.

As used herein “pERK activity profile” refers to the level of activationor phosphorylation of ERK (“pERK”) compared to the level ofnon-activated or non-phosphorylated ERK in a given sample. In oneexample, the sample is a solid tumor cell or tissue, or a non-solidtumor cancer cell or tissue. The pERK activity profile can be expressedin terms of a ratio (e.g., amount of pERK in a cancer cell treated witha compound of formula (I) divided by amount of non-phosphorylated ERK ina cancerous cell of the same type that was not treated with a compoundof formula (I)). In a typical measurement of pERK activity profiles,each treatment or patient sample and the untreated control samples arenormalized against total ERK (i.e., phosphorylated ERK plusnon-phosphorylated ERK). The normalized amount of pERK in each treatmentor patient sample is then divided by the amount of pERK in the untreatedcontrol sample, and this number is multiplied by 100 to obtain thepercent remaining in pERK activity for a given sample. The percentremaining can then be subtracted from 100 to give the percent reductionin pERK activity. The pERK activity profile may also be expressed interms of the level of activation of the pathway by measuring amounts ofphosphorylated downstream targets of ERK. A “reduced pERK activityprofile” refers to activation or phosphorylation levels of overall ERKin a sample that are lower than a baseline value. Such a baseline valuemay be determined based on the basal levels of a single cell type.Alternatively, a baseline value may be based on the average or meanlevel of pERK in a given population of sample cells. In one example, fora pERK activity profile as used herein refers to an average value basedon the pERK activity profile of tumor cells from patients which areuntreated with a compound of the invention.

One of the proteins measured to determine efficacy of compounds offormula (I) is phospho-S6 ribosomal protein (pS6RP). Alternatively, inorder to determine pS6K activity, a serine/threonine protein kinase pS6K(which encodes alternative isoforms P70^(S6K) or P85^(S6K)) is measured.As used herein “pS6RP or pS6K activity profile” refers to the level ofactivation or phosphorylation of S6RP or S6K (“pS6RP or pS6K”) comparedto the level of non-activated or non-phosphorylated S6RP or S6K in agiven sample. In one example, the sample is a solid tumor cell or tissueor a non-solid tumor cancer cell or tissue. The pS6RP or pS6K activityprofile can be expressed in terms of a ratio (e.g., amount of pS6RP orpS6K in a cancer cell treated with a compound of formula (I) divided byamount of non-phosphorylated S6RP or S6K in a cancerous cell of the sametype that was not treated with a compound of formula (I)). In a typicalmeasurement of pS6RP or pS6K activity profiles, each treatment orpatient sample and the untreated control samples are normalized againsttotal S6RP or S6K (i.e., phosphorylated S6RP or S6K plusnon-phosphorylated S6RP or S6K). The normalized amount of pS6RP or pS6Kin each treatment or patient sample is then divided by the amount ofpS6RP or pS6K in the untreated control sample, and this number ismultiplied by 100 to obtain the percent remaining in pS6RP or pS6Kactivity for the given treatment or patient sample. The percentremaining can then be subtracted from 100 to give the percent reductionin pS6RP or pS6K activity. The pS6RP or pS6K activity profile may alsobe expressed in terms of the level of activation of the pathway bymeasuring amounts of phosphorylated downstream targets of S6RP or S6K.For example, S6RP is downstream of S6K, and phosphorylation levels ofS6RP can be used a measure of pS6K activity. A “reduced pS6RP or pS6Kactivity profile” refers to activation or phosphorylation levels ofoverall pS6RP or pS6K in a sample that are lower than a baseline value.Such a baseline value may be determined based on the basal levels of asingle cell type. Alternatively, a baseline value may be based on theaverage or mean level of pS6RP or pS6K in a given population of samplecells. In one example, for a pS6RP or pS6K activity profile as usedherein refers to an average value based on the pS6RP or pS6K activityprofile of cancer cells from patients which are untreated with acompound of the invention.

Any suitable technique for showing reduced activity of these biomarkerscan be used in the methods of invention; for example, by detecting theproteins by traditional Western blot assay (see, e.g., the AKT WesternBlot Assay Kits (Cell Signaling Technology, Danverse, Mass.) or with anIn-Cell Western (ICW) assay, as shown in Example 90 below. See also thetechniques described in Falchook et al, Lancet (2012), 379:1893-1901.Additionally, methods for measuring levels of AKT activation and amountsof pAKT in a sample are known. For example, immunoprecipitation assayssuch as, e.g., the AKT Activity Assay Kits (abeam, San Francisco,Calif.), a chemoluminescence-linked immunosorbent assay (Cicenas et al,Breast Can Res., 7(4): R394 (2005), or the AlphaScreen SureFire Aktl(p-Thr308) Assay Kit (Perkin-Elmer, Waltham, Mass.) may be used. Othercommercially available assay kits include the pS6RP kit from iHistochem(San Diego, Calif.] and the pERK assay kits (MesoScale, CA). Still othertechniques or kits will be readily apparent to one of skill in the art.

A method for treating a condition treatable by inhibiting theRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways, comprisingadministering a first dosage amount of a one or more compounds offormula (I) to a patient; assaying a sample from the patient followingadministration of the compound to determine if the activity level ofpERK, pS6RP or pS6K or pAKT or a combination thereof has been reduced bya predetermined activity level as compared to the activity in anuntreated patient; and administering a second dosage amount of the oneor more compounds of formula (I) to the patient. The first and seconddosage amounts may be the same and in the range of about 0.01 mg/kg to500 mg/kg body weight. Alternatively, within this range, the first andsecond dosages may be ascending or descending doses. For example, if asecond dosage amount may be higher than a first dosage amount (i.e.,ascending). Alternatively, a second dosage amount may be lower than afirst dosage amount (i.e., a descending dose), is at the lower about0.01 mg/kg to about 0.1 mg, a second dosage amount may be a higher doseabout 1 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about100 μg/kg, about 75 μg/kg, about 50 μg/kg, about 25 μg/kg, about 10μg/kg, or about 1 g/kg.

As used herein, an “untreated patient” refers to a patient who has notbeen administered a therapeutically effective amount of one or more ofthe compounds of formula (I).

Also described herein is a method for monitoring the efficacy of acompound of formula (I) which involves administering a first dosageamount of at least one compound of formula (I) to a patient, assaying asample from the patient following administration of the compound todetermine if the activity level of pERK, pS6RP or pS6K or pAKT or acombination thereof has been reduced by a predetermined activity levelas compared to the activity in an untreated patient; and administering asecond dosage amount of the compound.

When monitoring the efficacy of therapy, the sample obtained from thepatient may include a variety of samples including, e.g., whole blood orblood derivatives (e.g., plasma, peripheral blood), lymphatic fluids, ortissue samples, may be selected.

The method described herein allow therapy to be customized to the needsof an individual subject, where desired, by allowing adjustment of dosesupward, downward, or to be retained at a flat (unchanged) dose dependingupon the needs of the individual. Thus, a first dosage and a seconddosage following assaying a sample from the patient may be ascendingdoses, flat doses, or descending doses as needed.

The following examples are illustrative only and are not intended tolimit the present invention.

EXAMPLES Preparation 1:N-(2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide

Step 1: 3-bromo-2-fluoroaniline

To a stirred solution of 3-bromo-2-fluoro benzoic acid (10 g, 0.04566mol) in N,N-dimethyl formamide (80 mL), were added dropwisetriethylamine (19 mL, 0.13669 mol) and diphenylphosphoryl azide (14.8mL, 0.05378 mol) at 0° C. sequentially. The reaction mixture was stirredfor 2 h at 0° C. Water (27 mL) was added and the reaction mixture washeated at 80° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with water (200 mL) and extracted with diethylether (3×150 mL). The combined organic layers were washed with coldwater (2×200 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The residue obtained was treated with hexane(100 mL), filtered, and the filter cake was washed with hexane (2×100mL). The filtrate was evaporated under reduced pressure to afford thetitle compound (4.3 g, 50%) as a brown liquid. ¹H NMR (400 MHz,DMSO-d₆): δ 6.82-6.70 (m, 3H), 5.43 (brs, 2H); ESI-MS: Calculated mass:188.96; Observed mass: 188.10 [M−H]⁻.

Step 2: N-(3-bromo-2-fluorophenyl)propane-1-sulfonamide

To a stirred solution of 3-bromo-2-fluoroaniline (1.8 g, 0.00952 mol) inDCM (18 mL) were added dropwise pyridine (1.35 mL, 0.017 mol) andpropane sulfonyl chloride (1.57 mL, 0.017 mol) at room temperature. Thereaction mixture was stirred overnight at the same temperature. Thereaction mixture was diluted with water (50 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were washed with1N HCl (25 mL), brine solution and dried over anhydrous sodium sulfate,then filtered. The filtrate was evaporated under reduced pressure. Thecrude product was purified using column chromatography (100-200 meshsilica gel; 2% EtOAc in hexane) to afford the title compound (700 mg,25%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.85 (s, 1H), 7.52 (t, J=8.4 Hz, 1H),7.42 (t, J=8.4 Hz, 1H), 7.14 (t, J=8.40 Hz, 1H), 3.32-3.10 (m, 2H),1.76-1.70 (m, 2H), 0.97 (t, J=7.2 Hz, 3H); ESI-MS: Calculated mass:294.96; Observed mass: 296.0 [M+H]⁺.

Step 3:N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide

A 100 mL round bottom flask was charged withN-(3-bromo-2-fluorophenyl)propane-1-sulfonamide (0.65 g, 0.0022 mol),toluene (20 mL), potassium acetate (0.64 g, 0.0066 mol) andbis(pinacolato)diboron (0.83 g, 0.0033 mol). The reaction mixture wasdegassed with nitrogen for 15 min. To this mixture was addedPd(dppf)Cl₂.DCM (89 mg, 0.00011 mol) and the mixture was degassed againwith nitrogen for 5 min. The reaction mixture was stirred overnight at100° C. The reaction mixture was filtered through the Celite® reagent,the filter cake was washed with ethyl acetate (50 mL), and the filtratewas evaporated under reduced pressure. The residue obtained was washedwith n-hexane (50 mL) and dried under vacuum to provide the titlecompound as a solid. The crude product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 9.59 (brs, 1H), 7.53(t, J=8.0 Hz, 1H), 7.44 (t, J=7.2 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 3.06(t, J=7.6 Hz, 2H), 1.78-1.68 (m, 2H), 1.30 (s, 12H), 0.96 (t, J=8.0 Hz,3H); ESI-MS: Calculated mass: 343.14; Observed mass: 342.20 [M−H]⁻.

Preparation 2:3-Fluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide

Step 1: 3-fluoropropyl methanesulfonate

To a stirred solution of 3-fluoro propanol (15 g, 0.19208 mol) indichloromethane (210 mL) were added drop wise triethylamine (32 mL,0.2302 mol) followed by methananesulfonyl chloride (16.3 mL, 0.21068mol) at 0° C. and the reaction mixture was stirred for 3 h at 0° C. Thereaction mixture was diluted with water (150 mL) and extracted with DCM(2×150 mL). The combined organic layers were washed with saturatedsodium bicarbonate solution, followed by brine solution and dried overanhydrous sodium sulfate, then filtered. The filtrate was evaporated andthe crude product was purified using column chromatography (100-200 meshsilica gel, 30% EtOAc in hexane) to afford the title compound (20 g,66%). ¹H NMR (400 MHz, DMSO-d₆): δ 4.60 (t, J=6.0 Hz, 1H), 4.48 (t,J=6.0 Hz, 1H), 4.29 (t, J=6.4 Hz, 2H), 3.18 (s, 3H), 2.12-2.0 (m, 2H).

Step 2: (3-Fluoropropyl)ethanethioate

To a stirred solution of 3-fluoropropyl methanesulfonate (20 g, 0.12807mol) in dimethyl sulfoxide (200 mL) was added potassium thioacetate(17.5 g, 0.15323 mol) at room temperature and the reaction mixture wasstirred for 12 h at room temperature. Water (300 mL) was added and thereaction mixture was extracted with diethyl ether (3×150 mL). Thecombined organic layers were washed with brine solution and dried overanhydrous sodium sulfate, then filtered. The filtrate was evaporatedunder reduced pressure to afford the title compound (15 g, 86%). ¹H NMR(400 MHz, DMSO-d₆): δ 4.52 (t, J=5.6 Hz, 1H), 4.40 (t, J=6.0 Hz, 1H),2.91 (t, J=7.6 Hz, 2H), 2.33 (s, 3H), 1.94-1.84 (m, 2H).

Step 3: 3-fluoropropane-1-sulfonyl chloride

Chlorine gas was passed through a stirred solution of(3-fluoropropyl)ethanethioate (15 g) in a 1:1 mixture of DCM and water(150 mL) at −20° C. for 3 h (until the aqueous color changed to green).The flow of chlorine gas was stopped and reaction mixture was maintainedat −20° C. for 2 more h. After confirming the completion of reaction byTLC, reaction mixture was extracted with DCM (2×300 mL). The combinedorganic layers were washed with 10% sodium bisulfite solution (2×200 mL)followed by brine solution and dried over anhydrous sodium sulfate, thenfiltered. The filtrate was evaporated under reduced pressure to affordthe title compound (13 g, 73%). ¹H NMR (400 MHz, DMSO-d₆): δ 4.58 (t,J=6.0 Hz, 1H), 4.46 (t, J=5.6 Hz, 1H), 2.70 (t, J=7.2 Hz, 2H), 2.05-1.92(m, 2H).

Step 4: N-(3-bromo-2-fluorophenyl)-3-fluoropropane-1-sulfonamide

To a stirred solution of 3-bromo-2-fluoroaniline (3 g, 0.0158 mol) indichloromethane (300 mL) were added dropwise pyridine (12.53 mL, 0.158mol) and 3-fluoropropane-1-sulfonyl chloride (7.64 mL, 0.047 mol) at 0°C. To the resulting mixture was added DMAP (0.387 g, 0.00317 mol) at 0°C. The reaction mixture was stirred overnight at room temperature. Water(500 mL) was added and the reaction mixture was extracted with DCM(2×100 mL). The combined organic layers were washed with 1N HCl (50 mL)followed by brine and dried over anhydrous sodium sulfate, thenfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using column chromatography (100-200 meshsilica gel, 10% EtOAc in hexane) to afford the title compound (3.4 g,69%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.99 (s, 1H), 7.54 (t, J=7.6 Hz, 1H),7.42 (t, J=8.4 Hz, 1H), 7.16 (t, J=8.4 Hz, 1H), 4.61 (t, J=3.2 Hz, 1H),4.49 (t, J=4.0 Hz, 1H), 3.25 (t, J=5.6 Hz, 2H), 2.16-2.03 (m, 2H);ESI-MS: Calculated mass: 312.96; Observed mass: 314.0 [M+H]⁺.

Step 5:3-fluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide

A 250 mL round bottom flask was charged withN-(3-bromo-2-fluorophenyl)-3-fluoropropane-1-sulfonamide (3.4 g, 0.0108mol), bis(pinacolato)diboron (4.13 g, 0.0162 mol) potassium acetate(3.19 g, 0.032 mol) and toluene (90 mL). The reaction mixture wasdegassed with nitrogen for 15 min. To the mixture was addedPd(dppf)Cl₂.DCM (883 mg, 0.00108 mol) and the mixture was degassed withnitrogen again for 10 min and stirred overnight at 100° C. The reactionmixture was cooled to room temperature, filtered through the Celite®reagent and the filter cake was washed with ethyl acetate (500 mL). Thefiltrate was evaporated under reduced pressure and the crude residue waswashed with n-hexane (2×50 mL). The residue was dried under vacuum toafford the title compound (4 g, crude). The crude product was used inthe next step without any further purification. ESI-MS: Calculated mass:361.13; Observed mass: 360.2 [M−H]⁻.

Preparation 3: N-(3-Bromo-2,4-difluorophenyl)propane-1-sulfonamide

Step 1: 2-Bromo-1,3-difluoro-4-nitrobenzene

A mixture of concentrated HNO₃ (6 mL, 0.143 mol) and concentrated H₂SO₄(6 mL, 0.111 mol) was added dropwise to a stirred solution of2-bromo-1,3-difluorobenzene (10 g, 0.057 mol) in concentrated H₂SO₄ (30mL, 0.56 mol) at 0° C. After the addition was complete, the reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas then neutralized to pH 7 with saturated sodium hydroxide solutionand extracted with ethyl acetate (2×250 mL). The combined organic layerswere dried, filtered and evaporated to provide the title compound (8.75g, 71%). ¹H NMR (400 MHz, CDCl₃): δ 8.15-8.10 (m, 1H), 7.15-7.11 (m,1H); ESI-MS: Calculated mass: 236.92; Observed mass: 235.90 [M−H]⁻.

Step 2: 3-Bromo-2,4-difluoroaniline

A mixture of 2-bromo-1,3-difluoro-4-nitrobenzene (8.5 g, 0.035 mol),concentrated HCl (24 mL, 0.789 mol), SnCl₂.2H₂O (24.3 g, 0.107 mol) anda small amount of diethyl ether (10 mL) was heated in an oil bath at 60°C. for 40 min. The reaction mixture was then cooled, neutralized withsaturated sodium hydroxide solution and extracted with ethyl acetate(2×250 mL). The combined organic layers were dried, filtered andevaporated to provide the title compound as a solid (9.51 g, crude). ¹HNMR (400 MHz, DMSO-d₆): δ 6.95 (t, J=8.8 Hz, 1H), 6.80-6.74 (m, 1H),5.27 (brs, 2H); ESI-MS: Calculated mass: 206.95; Observed mass: 206.0[M−H]⁻.

Step 3: N-(3-Bromo-2,4-difluorophenyl)propane-1-sulfonamide

To a stirred solution of 3-bromo-2,4-difluoroaniline (1.93 g, 0.0093mol) in dichloromethane (20 mL) were added dropwise pyridine (1.5 mL,0.0186 mol), propane-1-sulfonyl chloride (1.98 g, 0.0139 mol) and DMAP(113 mg, 0.0009 mol) at 0° C. The reaction mixture was stirred overnightat room temperature. Water (20 mL) was added and the reaction mixturewas extracted with dichloromethane (2×50 mL). The combined organiclayers were washed with 1N HCl (20 mL) then brine solution, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the crude product was purified using columnchromatography (100-200 mesh silica gel, 10% EtOAc in hexane) to affordthe title compound (2.5 g, 86%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.81 (s,1H), 7.49-7.43 (m, 1H), 7.28-7.23 (m, 1H), 3.11-3.07 (m, 2H), 1.78-1.69(m, 2H), 0.97 (t, J=7.2 Hz, 3H).

Preparation 4:1-Methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

Step 1: 1-(4-Bromophenyl)-3-methylurea

To a stirred solution of 4-bromophenylisocyanate (3 g, 0.01515 mol) inacetonitrile (40 mL) was added dropwise saturated aqueous methylamine(60 mL) at room temperature and stirring continued for 10 min at roomtemperature. A white solid was separated which was filtered, washed withhexane (30 mL) and dried under vacuum to afford the title compound (4.1g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (s, 1H), 7.36 (s, 4H), 6.03-6.02(m, 1H), 2.62 (d, J=4.8 Hz, 3H); ESI-MS: Calculated mass: 227.99;Observed mass: 229.0 [M+H]⁺.

Step 2:1-Methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea

A 250 mL round bottom flask was charged with1-(4-bromophenyl)-3-methylurea (4 g, 0.01789 mol),bis(pinacolato)diboron (5.9 g, 0.02323 mol), KOAc (5.2 g, 0.05306 mol)and toluene (70 mL). The reaction mixture was degassed with nitrogen for15 min and to the mixture was added Pd(dppf)Cl₂DCM (430 mg, 0.00052mol), and the resulting mixture was degassed with nitrogen again for 5min and stirred overnight at 100° C. The reaction mixture was cooled toroom temperature, filtered through the Celite® reagent and the filtercake was washed with ethyl acetate (2×50 mL). The filtrate wasevaporated under reduced pressure and the crude residue was purifiedusing column chromatography (100-200 mesh silica gel, 2% MeOH in DCM) toafford the title compound (2 g, 40%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.63(s, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 6.05 (d, J=4.4Hz, 1H), 2.63 (d, J=4.4 Hz, 3H), 1.26 (s, 12H); ESI-MS: Calculated mass:276.16; Observed mass: 277.20 [M+H]⁺.

Preparation 5:1-Methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea

Step 1: Phenyl (5-bromopyridin-2-yl)carbamate

To a stirred solution of 5-bromopyridin-2-amine (1 g, 0.00578 mol) indichloromethane (40 mL) were added dropwise diisopropylethylamine (2 mL,0.01156 mol) and phenylchloroformate (0.87 mL, 0.00693 mol) sequentiallyat 0° C. and stirring was continued for 2 h at room temperature. Water(10 mL) was added to the reaction mixture, the obtained solid wasfiltered and dried to afford the title compound (1 g, 59%). ¹H NMR (400MHz, DMSO-d₆): δ 10.93 (brs, 1H), 8.45 (brs, 1H), 8.02 (d, J=8.80 Hz,1H), 7.80 (d, J=8.80, 1H), 7.46-7.42 (m, 2H), 7.30-7.22 (m, 3H).

Step 2: 1-(5-Bromopyridin-2-yl)-3-methylurea

A sealed tube was charged with phenyl (5-bromopyridin-2-yl)carbamate (1g, 0.00341 mol) and 2M methylamine in THF (17 mL, 0.0341 mol). Thereaction mixture was stirred for 5 h at 100° C. The reaction mixture wasconcentrated under vacuum, and the residue was dissolved indichloromethane (50 mL) then washed with 1N sodium hydroxide solution(10 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure to afford the titlecompound (650 mg, 82%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.32 (brs, 1H),8.27 (d, J=2.4 Hz, 1H), 7.87 (dd, J′=8.80 Hz, J″=2.4 Hz, 1H), 7.47-7.45(m, 2H), 2.70 (d, J=4.4 Hz, 3H); LC-MS: Calculated mass: 228.99;Observed mass: 230.10 [M+H]⁺.

Step 3:1-Methyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea

A 100 mL round bottom flask was charged with1-(5-bromopyridin-2-yl)-3-methylurea (650 mg, 0.0028 mol), KOAc (830 mg,0.00846 mol), bis(pinacolato)diboron (930 mg, 0.0036 mol) and toluene(15 mL). The reaction mixture was degassed with nitrogen for 10 min. Tothis was added Pd(dppf)Cl₂.DCM (231 mg, 0.00028 mol) again degassed withnitrogen for 10 min and stirred for 16 h at 100° C. The reaction mixturewas filtered through the Celite® reagent and washed with EtOAc (100 mL).The filtrate was evaporated under reduced pressure and the residue waswashed with n-hexane (30 mL) to afford the title compound (300 mg, 38%).H NMR (400 MHz, DMSO-d₆): δ 9.43 (brs, 1H), 8.38 (s, 1H), 7.83 (dd,J′=8.40 Hz, J″=2.0 Hz, 1H), 7.55-7.49 (m, 1H), 7.32 (d, J=8.40 Hz, 1H),2.72 (d, J=4.40 Hz, 3H), 1.35 (s, 12H).

Preparation 6:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine

Step 1: 5-Bromo-4-(trifluoromethyl)pyridin-2-amine

To a stirred solution of 4-(trifuloromethyl)pyridine-2amine (2.5 g,0.01542 mol) in dichloromethane (250 mL) was added N-bromosuccinimide(2.74 g, 0.01542 mol) in portions under dark conditions at roomtemperature and stirring was continued at room temperature for 6 h. Thereaction mixture was diluted with 1N NaOH solution (20 mL) and extractedwith DCM (2×100 mL). The combined organic layers were dried over sodiumsulfate, filtered and evaporated under reduced pressure to afford thetitle compound (3.2 g, 86%). H NMR (400 MHz, CDCl₃): δ 8.28 (s, 1H),6.77 (s, 1H), 4.73 (brs, 2H); ESI-MS: Calculated mass: 239.95; Observedmass: 239.10 [M−H]⁻.

Step 2:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine

A 250 mL round bottom flask was charged with5-bromo-4-(trifluoromethyl)pyridin-2-amine (3.2 g, 0.013 mol),bis(pinacolato)diboron (4.74 g, 0.0186 mol), KOAc (5.22 g, 0.053 mol)and 1,4-dioxane (100 mL). The reaction mixture was degassed withnitrogen for 15 min and to the mixture was added Pd(dppf)Cl₂.DCM (544mg, 0.00066 mol). The resulting mixture was degassed with nitrogen againfor 10 min and stirring continued overnight at 100° C. The reactionmixture was cooled to room temperature, filtered through the Celite®reagent and the filter cake was washed with EtOAc (300 mL). The filtratewas evaporated under reduced pressure to afford the title compound (5 g,crude). The crude product was used in the next step without furtherpurification. ESI-MS: Calculated mass: 288.13; Observed mass: 289.0[M+H]⁺.

Preparation 7:1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

Step 1: 2-Bromo-6-fluorobenzaldehyde

To a stirred solution of diisopropylamine (1.4 mL, 0.00571 mol) in drytetrahydrofuran (7.2 mL) was added dropwise n-butyllithium (1.6M inhexane) (3.56 mL, 0.00571 mol) at 0° C. and stirring was continued for15 min at 0° C. The reaction mixture was cooled to −78° C. and1-bromo-3-fluorobenzene (1 g, 0.00571 mol) was added over 10 min. Afterstirring for 1 h at −78° C., anhydrous N,N-dimethylformamide (7.2 mL)was added dropwise over 5 min and the resulting mixture was stirred foranother 20 min at −78° C. The reaction was quenched with addition ofacetic acid (0.6 mL) followed by water (15 mL) and the mixture waswarmed to room temperature. The mixture was extracted with ethyl acetate(2×20 mL) and the combined organic layers were washed with water (2×10mL) followed by brine solution and dried over anhydrous sodium sulfate.The solvent was evaporated under vacuum to afford the title compound asa pale yellow solid (850 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.21(s, 1H), 7.66-7.61 (m, 2H), 7.45-7.42 (m, 1H). ESI-MS: Calculated mass:201.94; Observed mass: 202.0 [M]⁺.

Step 2: 4-Bromo-1H-indazole

To a stirred solution of 2-bromo-6-fluorobenzaldehyde (850 mg, 0.004mol) in DMSO (1 mL) was added hydrazinehydrate (4.5 mL) at roomtemperature and the resulting mixture was stirred overnight at 80° C.The reaction mixture was cooled to room temperature, water (10 mL) wasadded and the mixture was extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with brine solution, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to afford the title compound as a yellow solid (700 mg,84%). %). ¹H NMR (400 MHz, DMSO-d₆): δ 13.44 (brs, 1H), 8.03 (s, 1H),7.57 (d, J=8.0 Hz, 1H), 7.34 (d, J=7.20 Hz, 1H), 7.28 (t, J=7.60 Hz,1H); ESI-MS: Calculated mass: 195.96; Observed mass: 197.0 [M+H]⁺.

Step 3: 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a stirred solution of 4-bromo-1H-indazole (700 mg, 0.003645 mol) inN,N-dimethylformamide (10 mL) were added 3,4-dihydro-2H-pyran (0.4 mL,0.004375 mol) and para toluene sulfonic acid (1.04 g, 0.005467 mol). Thereaction mixture was stirred overnight at 70° C., cooled to roomtemperature, diluted with water (50 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine solution,dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure and the crude product was purifiedusing column chromatography (100-200 mesh silica gel, 15% EtOAc inhexane) to afford the title compound (550 mg, 53%). ¹H NMR (400 MHz,DMSO-d₆): δ 8.08 (s, 1H), 7.78 (d, J=8.40 Hz, 1H), 7.42 (d, J=7.20 Hz,1H), 7.35 (t, J=8.40 Hz, 1H), 5.80 (dd, J′=9.6 Hz, J″=2.80 Hz, 1H),3.89-3.86 (m, 1H), 3.77-3.71 (m, 1H), 2.49-2.32 (m, 1H), 2.06-1.95 (m,2H), 1.77-1.60 (m, 1H), 1.59-1.56 (m, 2H).

Step 4:1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

A 50 mL round bottom flask was charged with4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (550 mg, 0.001956 mol),KOAc (575 mg, 0.00586 mol), bis(pinacolato)diboron (645 mg, 0.002543mol) and 1,4-dioxane (10 mL). The reaction mixture was degassed withnitrogen for 20 min and to the reaction mixture was addedPd(dppf)Cl₂.DCM (159 mg, 0.00019 mol). The resulting mixture wasdegassed with nitrogen again for 10 min and was stirred overnight at100° C. The reaction mixture was filtered through Celite® reagent andwashed with ethyl acetate (30 mL). The filtrate was evaporated and thecrude product was purified using column chromatography (100-200 meshsilica gel, 20% EtOAc in hexane) to afford the title compound as aliquid (590 mg, 91%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.20 (s, 1H), 7.87(d, J=8.0 Hz, 1H), 7.54 (d, J=5.6 Hz, 1H), 7.43 (t, J=6.8 Hz, 1H), 5.86(dd, J′=9.20 Hz, J″=2.4 Hz, 1H), 3.89-3.86 (m, 1H), 3.77-3.70 (m, 1H),2.54-2.40 (m, 1H), 2.05-1.92 (m, 2H), 1.77-1.60 (m, 1H), 1.59-1.57 (m,2H), 1.35 (s, 12H); ESI-MS: Calculated mass: 328.20; Observed mass:329.0 [M+H]⁺.

Preparation 8: 2-(Difluoromethyl)-1H-benzo[d]imidazole

To a stirred solution of O-phenylenediamine (1 g, 0.00925 mol) in 4N HCl(10 mL) was added difluoroacetic acid (0.977 g, 0.01018 mol) and theresulting mixture was heated at reflux for 2 h. The reaction mixture wascooled to room temperature, neutralized with sodium carbonate and thesolid obtained was collected by filtration and washed with water (30mL), then dried under vacuum to afford the title compound (1 g, 64%). HNMR (400 MHz, CDCl₃): δ 10.64 (brs, 1H), 7.82-7.57 (m, 2H), 7.37 (dd,J′=6.0 Hz, J″=3.20 Hz, 2H), 6.92 (t, J=53.6 Hz, 1H); ESI-MS: Calculatedmass: 168.05; Observed mass: 169.0 [M+H]⁺.

Preparation 9:2-(((Tert-butyldimethylsilyl)oxy)methyl)-1H-benzo[d]imidazole

Step 1: (1H-Benzo[d]imidazol-2-yl)methanol

To a stirred solution of O-phenylenediamine (5 g, 0.046 mol) in 4N HCl(50 mL) was added 2-hydroxyacetic acid (4.2 g, 0.0555 mol) and stirringwas continued for 3 h at 100° C. The reaction mixture was cooled to roomtemperature, neutralized with saturated sodium bicarbonate solution andthe solid obtained was collected by filtration and dried to afford thetitle compound (3.5 g, 73%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.28 (brs,1H), 7.52-7.44 (m, 2H), 7.12 (d, J=4.80 Hz, 2H), 5.66 (t, J=6.0 Hz, 1H),4.68 (d, J=5.2 Hz, 2H).

Step 2:2-(((Tert-butyldimethylsilyl)oxy)methyl)-1H-benzo[d]imidazole

To a stirred solution of (1H-benzo[d]imidazol-2-yl)methanol (2 g, 0.0135mol) in pyridine (30 mL) was added tert-butyl dimethylsilyl chloride(3.46 g, 0.02296 mol) at room temperature and stirring was continued for4 h at room temperature. The pyridine was evaporated under vacuum, andthe residue was taken up in dichloromethane (50 mL). The organic layerwas washed with saturated sodium bicarbonate and brine solution, driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure and the crude product was purified using columnchromatography (100-200 mesh silica gel, 20% EtOAc in hexane) to affordthe title compound (3.1 g, 87%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.23(brs, 1H), 7.51 (brs, 2H), 7.15 (dd, J′=6.0 Hz, J′=2.80 Hz, 2H), 4.85(s, 2H), 0.90 (s, 9H), 0.10 (s, 6H); ESI-MS: Calculated mass: 262.15;Observed mass: 263.20 [M+H]⁺.

Example 1:2,6-Difluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)benzenesulfonamide

Step 1: 3-Hydroxy-2-nitrobenzoic acid

3-chloro-2-nitrobenzoic acid (30 g, 0.148 mol) was dissolved in aqueouspotassium hydroxide solution (240 g, 4.277 mol, in 300 mL H₂O) at roomtemperature and then heated at 110° C. for 12 h. The reaction mixturewas cooled to room temperature, diluted with water, acidified with conc.HCl at 0° C. to pH 2, and extracted with ethyl acetate (2×500 mL). Thecombined organic layers were washed with brine solution, dried overanhydrous sodium sulfate, filtered and the filtrate was evaporated underreduced pressure to afford the title compound (27 g, 99%). ¹H NMR (400MHz, DMSO-d6): δ 13.8 (brs, 1H), 11.21 (s, 1H), 7.47 (t, J=8.0 Hz, 1H),7.39 (dd, J′=8.0 Hz, J″=1.6 Hz, 1H), 7.30 (dd, J′=7.6 Hz, J″=0.8 Hz,1H); ESI-MS: Calculated mass: 183.02; Observed mass: 182.10 [M−H]⁻.

Step 2: Methyl 3-methoxy-2-nitrobenzoate

To a stirred suspension of 3-hydroxy-2-nitrobenzoic acid (27 g, 0.147mol) and potassium carbonate (81.3 g, 0.589 mol) in N,N-dimethylformamide (270 mL) was added methyl iodide (36.87 mL, 0.589 mol)dropwise at 0° C. After the addition was complete, the reaction mixturewas stirred at room temperature overnight. The solid separated out afterthe addition of ice-cold water to the reaction mixture was collected byfiltration and dried to afford the title compound (27 g, 86%). ¹H NMR(400 MHz, DMSO-d₆): δ 7.72-7.64 (m, 2H), 7.58 (dd, J′=7.2 Hz, J″=1.2 Hz,1H), 3.92 (s, 3H), 3.83 (s, 3H); ESI-MS: Calculated mass: 211.05;Observed mass: 212.10 [M+H]⁺.

Step 3: Methyl 2-amino-3-methoxybenzoate

A mixture of methyl 3-methoxy-2-nitrobenzoate (27 g, 0.127 mol) and 10%Pd—C (13 g) in 500 mL of methanol was stirred at room temperature for 2h at 60 PSI in a Parr hydrogenation apparatus. After confirming thecompletion of reaction by TLC, the reaction mixture was filtered throughCelite® reagent and the Celite® reagent was washed with 20% MeOH inethyl acetate (2 L). The filtrate was concentrated under reducedpressure and the solid obtained was dried under high vacuum to affordthe title compound (22 g, 95%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.33 (dd,J′=8.4 Hz, J″=1.2 Hz, 1H), 6.97 (dd, J′=7.6 Hz, J″=0.8 Hz, 1H), 6.52 (t,J=8.4 Hz, 1H), 6.32 (brs, 2H), 3.81 (s, 3H), 3.72 (s, 3H); ESI-MS:Calculated mass: 181.07; Observed mass: 182.0 [M+H]⁺.

Step 4: Methyl 2-amino-5-bromo-3-methoxybenzoate

To a stirred solution of methyl 2-amino-3-methoxybenzoate (22 g, 0.121mol) in acetic acid (220 mL) was added bromine (7.5 mL, 0.145 mol)dropwise at 0° C. The reaction mixture was stirred at room temperaturefor 1 h. After the completion, the reaction mixture was poured into 1 Lof cold water and stirred for 30 min at room temperature and extractedwith ethyl acetate (2×500 mL). The combined organic layers were washedwith saturated sodium bicarbonate solution (2×1 L) followed by brinesolution, then dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure and the crude productwas purified using column chromatography (100-200 mesh silica gel, 10%EtOAc in hexane) to afford the title compound as a white solid (20 g,63% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.42 (d, J=2.0 Hz, 1H), 7.09(d, J=2.0 Hz, 1H), 6.47 (brs, 2H), 3.85 (s, 3H), 3.81 (s, 3H); ESI-MS:Calculated mass: 258.98; Observed mass: 260.10 [M+H]⁺.

Step 5: 6-Bromo-8-methoxyquinazoline-2,4(1H,3H)-dione

A mixture of urea (46 g, 0.768 mol) and methyl2-amino-6-bromo-3-methoxybenzoate (20 g, 0.076 mol) was heated at 180°C. for 6 h. After confirming the completion of reaction by TLC, thereaction mixture was allowed to cool to 60° C. and 250 mL of water wasadded. The aqueous reaction mixture was stirred at 60° C. for 30 min andthe solid was collected by filtration and dried under vacuum. The solidcompound obtained (20 g, 86%) was taken into the next step without anyfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 11.43 (brs, 1H),10.70 (brs, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.43 (d, J=1.6 Hz, 1H), 3.89(s, 3H); ESI-MS: Calculated mass: 269.96; Observed mass: 269.0 [M−H]⁻.

Step 6: 6-Bromo-2,4-dichloro-8-methoxyquinazoline

To a stirred suspension of 6-bromo-8-methoxyquinazoline-2,4(1H,3H)-dione(20 g, 0.074 mol) in 200 mL of phosphorousoxychloride (POCl₃) were addeddropwise diisopropyl ethylamine (10.7 mL, 0.059 mol) andN,N-dimethylformamide (3 mL) sequentially. The reaction mixture wasmaintained at 130° C. overnight. POCl₃ was removed by distillation andthe crude residue was azeotroped twice with toluene. The resulting crudeproduct was poured into ice-cold water (1 L) and stirred for 1 h at roomtemperature. The precipitated yellow solid was collected by filtrationand dried under vacuum to afford the title compound (18 g, 78%). ¹H NMR(400 MHz, DMSO-d₆): δ 7.92 (d, J=2.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H),4.04 (s, 3H); ESI-MS: Calculated mass: 305.90; Observed mass: 307.00[M+H]⁺.

Step 7: 4-(6-Bromo-2-chloro-8-methoxyquinazolin-4-yl)morpholine

To a stirred solution of 6-bromo-2,4-dichloro-8-methoxyquinazoline (18g, 0.058 mol) and diisoproylethylamine (30 mL, 0.174 mol) indichloromethane (180 mL) was added morpholine (5.1 mL, 0.058 mol)dropwise slowly at 0° C. After the addition was complete, the reactionmixture was stirred until TLC analysis indicated complete consumption ofstarting material (0° C. for 10 min). The reaction mixture was dilutedwith water (250 mL) and extracted with dichloromethane (2×500 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified using column chromatography (100-200 meshsilica gel, 30% EtOAc in hexane) to afford the title compound as ayellow solid (12 g, 57%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.63 (d, J=1.2Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 3.94 (s, 3H), 3.80-3.74 (m, 8H);ESI-MS: Calculated mass: 356.99; Observed mass: 358.0 [M+H]⁺.

Step 8:N-(3-(2-Chloro-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

To a 100 mL round bottom flask were added4-(6-bromo-2-chloro-8-methoxyquinazolin-4-yl)morpholine (250 mg, 0.7mmol), N,N-dimethylformamide (8 mL), water (2 mL),2,6-difluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) benzene sulfonamide (375 mg, 0.9 mmol) and sodium carbonate (150mg, 1.4 mmol). The reaction mixture was degassed with nitrogen for 10min. To this mixture was added Pd(PPh₃)₂C₂ (48 mg, 0.07 mmol) was addedand the resulting mixture was degassed again for 5 min. The reactionmixture was stirred at 80° C. for 3 h. Water (50 mL) was added to thereaction mixture followed by extraction with ethyl acetate (2×100 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified using column chromatography (100-200 meshsilica gel, 2% MeOH in DCM) to afford the title compound (175 mg, 44%).¹H NMR (400 MHz, DMSO-d₆): δ 10.9 (s, 1H), 7.77-7.70 (m, 1H), 7.55 (t,J=7.68 Hz, 1H), 7.49 (s, 1H), 7.37-7.25 (m, 5H), 3.94 (s, 3H), 3.81-3.73(m, 8H); ESI-MS: Calculated mass: 564.08; Observed mass: 565.20 [M+H]⁺.

Step 9:2,6-Difluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)benzenesulfonamide

To a 100 mL round bottom flask, were addedN-(3-(2-chloro-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide(175 mg, 0.31 mmol), N,N-dimethylformamide (8 mL), water (2 mL),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(130 mg, 0.46 mmol) and sodium carbonate (131 mg, 1.24 mmol). Thereaction mixture was degassed with nitrogen for 10 min. To this mixturewas added Pd(PPh₃)₂Cl₂ (21 mg, 0.03 mmol) and the resulting mixture wasdegassed with nitrogen again for 5 min. The reaction mixture was stirredovernight at 80° C. Water (50 mL) was added to the reaction mixturefollowed by extraction with ethyl acetate (2×100 mL). The organic layerwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedusing column chromatography (100-200 mesh silica gel, 3% MeOH in DCM) toafford the title compound (80 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆): δ10.89 (s, 1H), 8.79 (s, 1H), 8.35 (d, J=8.8 Hz, 2H), 7.74-7.70 (m, 1H),7.57-7.53 (m, 3H), 7.49 (s, 1H), 7.35-7.28 (m, 4H), 7.21 (s, 1H),7.09-7.08 (m, 1H), 4.0 (s, 3H), 3.80-3.75 (m, 8H), 2.66 (d, J=4.4 Hz,3H); ESI-MS: Calculated mass: 678.19; Observed mass: 679.3 [M+H]⁺.

Example 2:N-(3-(2-(1H-indazol-4-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

To a stirred solution ofN-(2-fluoro-3-(8-methoxy-4-morpholino-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)quinazolin-6-yl)phenyl)propane-1-sulfonamide(200 mg, 0.312 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (3 mL) dropwise at room temperature and the reaction mixture wasstirred for 1 h at room temperature. The reaction mixture was evaporatedunder reduced pressure, the residue was neutralized with saturatedsodium bicarbonate solution and then extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine solution, driedover anhydrous sodium sulfate, filtered and evaporated under reducedpressure. The crude product was purified using preparative HPLC toafford the title compound (26 mg, 14%). ¹H NMR (400 MHz, DMSO-d₆): δ13.21 (s, 1H), 9.75 (s, 1H), 9.17 (s, 1H), 8.37 (d, J=6.8 Hz, 1H), 7.72(s, 1H), 7.69 (s, 1H), 7.58 (t, J=7.2 Hz, 1H), 7.56-7.50 (m, 1H), 7.47(s, 2H), 7.34 (t, J=8.0 Hz, 1H), 4.12 (s, 3H), 3.86-3.84 (m, 8H),3.19-3.15 (m, 2H), 1.82-1.76 (m, 2H), 1.02-0.99 (m, 3H); ESI-MS:Calculated mass: 576.20; Observed mass: 577.40 [M+H]⁺.

Example 3:N-(3-(2-(6-((2-aminoethyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

A mixture ofN-(2-fluoro-3-(2-(6-fluoropyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide(190 mg) and ethylenediamine (1.9 mL) was heated at 70° C. for 1 h in asealed tube. After confirming completion of the reaction by TLC, thereaction mixture was directly evaporated under reduced pressure. Thecrude product was purified using preparative HPLC to afford the titlecompound (70 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.10 (s, 1H), 8.38(d, J=8.8 Hz, 1H), 7.58 (brs, 1H), 7.39 (t, J=7.2 Hz, 1H), 7.34 (s, 1H),7.14-7.07 (m, 3H), 7.59 (d, J=8.8 Hz, 1H), 4.01 (s, 3H), 3.80-3.77 (m,8H), 2.96 (t, J=7.2 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 2.79 (t, J=6.4 Hz,2H), 2.78-2.61 (m, 2H), 1.75-1.69 (m, 2H), 0.94-0.85 (m, 3H); ESI-MS:Calculated mass: 595.24; Observed mass: 596.2 [M+H]⁺.

Example 4:N-(3-(2-(6-aminopyridin-3-yl)-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

Step 1: 6-Bromo-2-chloro-4-morpholinoquinazolin-8-ol

To a stirred solution of4-(6-bromo-2-chloro-8-methoxyquinazolin-4-yl)morpholine (2 g, 0.0056mol) in dichloromethane (40 mL) was added borontribromide (8.42 g, 0.033mol) dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 16 h and poured into ice-cold water. The resultingmixture was neutralized with saturated sodium bicarbonate solution to pH7 and extracted with dichloromethane (2×100 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered and evaporatedunder reduced pressure to afford the title compound (800 mg, crude).This product was used in the next step without further purification.ESI-MS: Calculated mass: 342.97; Observed mass: 342.10[M−H]⁻.

Step 2: 2-((6-Bromo-2-chloro-4-morpholinoquinazolin-8-yl)oxy)ethanol

To a stirred suspension of 6-bromo-2-chloro-4-morpholinoquinazolin-8-ol(0.8 g, 0.0023 mol) and potassium carbonate (1.12 g, 0.0081 mol) inN,N-dimethylformamide (15 mL) was added 2-bromoethanol (0.43 g, 0.0034mol) at room temperature. The reaction temperature was increased to 80°C. and stirring was continued for another 18 h. Water (50 mL) was addedto the reaction mixture followed by extraction with ethyl acetate (3×50mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and evaporated. The crude product was purified usingcolumn chromatography (100-200 mesh silica gel; 2% MeOH in DCM) toafford the title compound (200 mg, 22%). ¹H NMR (400 MHz, DMSO-d₆): δ7.64 (d, J=1.2 Hz, 1H), 7.49 (d, J=1.68 Hz, 1H), 4.98 (t, J=5.2 Hz, 1H),4.18 (t, J=4.4 Hz, 2H), 3.82-3.74 (m, 10H); ESI-MS: Calculated mass:387.0; Observed mass: 388.20 [M+H]⁺.

Step 3:N-(3-(2-Chloro-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

A stirred mixture of2-((6-bromo-2-chloro-4-morpholinoquinazolin-8-yl)oxy)ethanol (0.2 g,0.000516 mol),N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(0.21 g, 0.00062 mol) and sodium carbonate (0.1 g, 0.001 mol) in 25 mLof DMF and H₂O (4:1 mixture) was degassed with nitrogen for 15 min. Tothis mixture was added Pd(PPh₃)₂Cl₂ (36 mg, 0.000051 mol) and theresulting mixture was degassed with nitrogen again for 10 min. Thereaction mixture was stirred at 80° C. for 1 h. The reaction mixture wascooled to room temperature, water (50 mL) was added and the resultingmixture was extracted with ethyl acetate (3×50 mL). The organic layerswere combined, washed with water followed by brine solution andconcentrated under reduced pressure. The crude product was purifiedusing column chromatography (100-200 mesh silica gel; 2% MeOH in DCM) toafford the title compound (180 mg, 66%). ¹H NMR (400 MHz, DMSO-d6): δ9.73 (d, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.64-7.47 (m, 3H), 7.34-7.29 (m,1H), 4.93 (t, J=5.2 Hz, 1H), 4.31 (t, J=4.8 Hz, 2H), 3.92-3.76 (m, 10H),3.17-3.10 (m, 2H), 1.8-1.74 (m, 2H), 1.01-0.96 (m, 3H); ESI-MS:Calculated mass: 524.13; Observed mass: 525.2 [M+H]⁺.

Step 4:N-(3-(2-(6-Aminopyridin-3-yl)-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

A stirred mixture ofN-(3-(2-chloro-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide(0.18 g, 0.00034 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (98 mg,0.00044 mol) and sodium carbonate (0.14 g, 0.0013 mol) in 25 mL of DMFand H₂O (4:1 mixture) was degassed with nitrogen for 15 min. To thismixture was added Pd(PPh₃)₂Cl₂ (24 mg, 0.000034 mol) and the resultingmixture was degassed with nitrogen again for 10 min. The reactionmixture was stirred at 80° C. for 1 h. The reaction mixture was cooledto room temperature, water (50 mL) was added and the resulting mixturewas extracted with ethyl acetate (3×50 mL). The organic layers werecombined, washed with water followed by brine solution and concentratedunder reduced pressure. The crude product was purified using preparativeHPLC to afford the title compound (8 mg, 4%). ¹H NMR (400 MHz, DMSO-d6):δ 9.72 (s, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.4 (dd, J′=8.8 Hz, J″=2.0 Hz,1H), 7.63 (s, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.46-7.43 (m, 2H), 7.31 (t,J=8.0 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.51 (brs, 2H), 4.98 (t, J=4.4Hz, 1H), 4.29 (t, J=4.8 Hz, 2H), 3.88-3.77 (m, 10H), 3.16 (t, J=8.0 Hz,2H), 1.81-1.73 (m, 2H), 1.05 (t, J=6.8 Hz, 3H); ESI-MS: Calculated mass:582.21; Observed mass: 583.1 [M+H]⁺.

Example 5:N-(3-(2-(6-aminopyridin-3-yl)-4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide

Step 1: 3-Morpholino-2-nitrobenzoic acid

A stirred mixture of 3-chloro2-nitrobenzoic acid (5 g, 0.024 mol) andmorpholine (40 mL) was heated at 130° C. for 48 h. The reaction mixturewas cooled to room temperature, water (150 mL) was added and theresulting mixture was acidified with 1N hydrochloric acid to pH 2. Thesolid separated after 1 h was collected by filtration and dried undervacuum to afford the title compound (6.2 g, 98%). ¹H NMR (400 MHz,DMSO-d₆): δ 13.9 (brs, 1H), 7.83-7.77 (m, 2H), 7.35 (t, J=7.6 Hz, 1H),3.65-3.62 (m, 4H), 2.90-2.88 (m, 4H); ESI-MS: Calculated mass: 252.07;Observed mass: 251.0 [M−H]⁻.

Step 2: Methyl 3-morpholino-2-nitrobenzoate

To a stirred suspension of 3-morpholino-2-nitrobenzoic acid (6.2 g,0.024 mol) and potassium carbonate (6.78 g, 0.049 mol) inN,N-dimethylformamide (62 mL), was added methyl iodide (6.98 g, 0.049mol) at 0° C. The reaction mixture was stirred for 3 h at roomtemperature. Ice-cold water (300 mL) was added and the resulting mixturewas stirred for 30 min at room temperature. The solid separated out wascollected by filtration and dried under vacuum to afford the titlecompound (5.6 g, 85%). ¹H NMR (400 MHz, DMSO-d6): δ 7.86 (dd, J′=7.6 Hz,J″=1.6 Hz, 1H), 7.79 (dd, J′=7.6 Hz, J″=1.6 Hz, 1H), 7.71 (t, J=8.4 Hz,1H), 3.83 (s, 3H), 3.65-3.63 (m, 4H), 2.91-2.89 (m, 4H).

Step 3: Methyl 2-amino-3-morpholinobenzoate

A mixture of methyl 3-morpholino-2-nitrobenzoate (5.6 g) and 10% Pd—C(1.5 g) in 56 mL of methanol was stirred for 2 h at 60 PSI hydrogenpressure in a Parr hydrogenation apparatus. After confirming completionof reaction by TLC, the reaction mixture was filtered through Celite®reagent and the Celite® reagent was washed with methanol (200 mL). Thefiltrate was concentrated under reduced pressure and the solid obtainedwas dried under high vacuum to afford the title compound (4.5 g, 97%).¹H NMR (400 MHz, DMSO-d₆): δ 7.52 (d, J=6.8 Hz, 1H), 7.17 (d, J=6.8 Hz,1H), 6.56 (t, J=7.68 Hz, 1H), 6.4 (brs, 2H), 3.79-3.75 (m, 7H),2.78-2.76 (m, 4H); ESI-MS: Calculated mass: 236.12; Observed mass:237.10 [M+H]⁺.

Step 4: Methyl 2-amino-5-bromo-3-morpholinobenzoate

To a stirred solution of methyl 2-amino-3-morpholinobenzoate (4.5 g,0.02044 mol) in acetic acid (45 mL) was added bromine (3.92 g, 0.024mol) dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 1 h. After the completion of the reaction, the reactionmixture was poured into 1 L of cold water and the resulting mixture wasstirred for 30 min at room temperature, then extracted with ethylacetate (2×500 mL). The combined organic layers were washed withsaturated sodium bicarbonate solution followed by brine solution, driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure and the crude product was purifiedusing column chromatography (100-200 mesh silica gel, 20% EtOAc inhexane) to afford the title compound (4.4 g, 68%). ¹H NMR (400 MHz,DMSO-d₆): δ 7.61 (d, J=2.0 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.50 (brs,2H), 3.80-3.75 (m, 7H), 2.80-2.78 (m, 4H); ESI-MS: Calculated mass:314.03; Observed mass: 313.20 [M−H]⁻.

Step 5: 6-Bromo-8-morpholinoquinazoline-2,4(1H,3H)-dione

A mixture of urea (8.4 g, 0.14 mol) and methyl2-amino-5-bromo-3-morpholinobenzoate (4.4 g, 0.014 mol) was heated at200° C. for 3 h. After confirming the completion of reaction by TLC, thereaction mixture was allowed to cool to 60° C. and 100 mL of water wasadded. The aqueous reaction mixture was stirred at 100° C. for 15 minand the solid was collected by filtration and dried under vacuum. Thesolid compound obtained (4 g, 86%) was taken into the next step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 7.73 (d, J=2.4 Hz,1H), 6.60 (d, J=2.4 Hz, 1H), 3.84-3.82 (m, 4H), 2.84-2.82 (m, 4H);ESI-MS: Calculated mass: 325.01; Observed mass: 324.0 [M−H]⁻.

Step 6: 4-(6-Bromo-2,4-dichloroquinazolin-8-yl)morpholine

To a stirred suspension of6-bromo-8-morpholinoquinazoline-2,4(1H,3H)-dione in 100 mL ofphosphorousoxychloride (POCl₃) were added dropwise diisopropylethylamine(1.41 g, 0.0109 mol) and N,N-dimethylformamide (2.5 ml) sequentially.The reaction mixture was maintained at 130° C. overnight. The excessPOCl₃ was removed by distillation and the crude residue was azeotropedwith toluene (2×100 mL). The resulting crude product was poured intoice-cold water and the precipitated solid was collected by filtrationand dried under vacuum to afford the title compound (4.4 g), which wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 7.93 (d, J=1.6 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 3.83-3.81(m, 4H), 3.40-3.38 (m, 4H).

Step 7: 4,4′-(6-Bromo-2-chloroquinazoline-4,8-diyl)dimorpholine

To a stirred solution of4-(6-bromo-2,4-dichloroquinazolin-8-yl)morpholine (4.4 g, 0.012 mol) anddiisoproylethylamine (4.71 g, 0.036 mol) in dichloromethane (130 mL) wasadded morpholine (1.062 g, 0.012 mol) dropwise slowly at 0° C. After theaddition was complete, the reaction mixture was stirred at 0° C. for 30min. The reaction mixture was diluted with water (200 mL) and extractedwith dichloromethane (2×500 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedusing column chromatography (100-200 mesh silica gel, 20% EtOAc inhexane) to afford the title compound (3.2 g, 64%). ¹H NMR (400 MHz,DMSO-d₆): δ 7.6 (d, J=2.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 3.80-3.73 (m,12H), 3.31-3.28 (m, 4H); ESI-MS: Calculated mass: 412.03; Observed mass:413.20 [M+H]⁺.

Step 8: 4,4′-(6-bromo-2-chloroquinazoline-4,8-diyl)dimorpholine

A stirred mixture of4,4′-(6-bromo-2-chloroquinazoline-4,8-diyl)dimorpholine (0.6 g, 0.0014mol),3-fluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(0.788 g, 0.00218 mol) and sodium carbonate (0.308 g, 0.0029 mol) in 30mL of DMF and H₂O (4:1 mixture) was degassed with nitrogen for 15 min.To this mixture was added Pd(PPh₃)₂Cl₂ (103 mg, 0.00014 mol) and theresulting mixture was degassed with nitrogen again for 10 min. Thereaction mixture was stirred at 80° C. for 1 h. The reaction mixture wascooled to room temperature, water (100 mL) was added and the resultingmixture was extracted with ethyl acetate (2×200 mL). The organic layerswere combined, washed with water followed by brine solution andconcentrated under reduced pressure. The crude product was purifiedusing column chromatography (100-200 mesh silica gel; 50% EtOAc inhexane) to afford the title compound (150 mg, 18%). ¹H NMR (400 MHz,DMSO-d₆): δ 9.86 (brs, 1H), 7.62 (s, 1H), 7.54 (t, J=6.4 Hz, 1H), 7.45(t, J=6.8 Hz, 1H), 7.31 (t, J=8.0 Hz, 2H), 6.62 (t, J=6.0 Hz, 1H), 4.5(t, J=6.0 Hz, 1H), 3.80-3.76 (m, 12H), 3.31-3.27 (m, 4H), 3.31-3.325 (m,2H), 2.17-2.10 (m, 2H); ESI-MS: Calculated mass: 567.15; Observed mass:566.30 [M−H]⁻.

Step 9: 4,4′-(6-Bromo-2-chloroquinazoline-4,8-diyl)dimorpholine

A stirred mixture ofN-(3-(2-chloro-4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide(0.15 g, 0.00026 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (75 mg,0.00034 mol) and sodium carbonate (0.112 g, 0.0010 mol) in 25 mL of DMFand H₂O (4:1 mixture) was degassed with nitrogen for 15 min. To thismixture was added Pd(PPh₃)₂Cl₂ (18 mg, 0.000026 mol) and the resultingmixture was degassed with nitrogen again for 10 min. The reactionmixture was stirred at 80° C. for 1 h. The reaction mixture was cooledto room temperature, water (50 mL) was added and the resulting mixturewas extracted with ethyl acetate (3×50 mL). The organic layers werecombined, washed with water followed by brine solution and concentratedunder reduced pressure. The crude product was purified using preparativeHPLC to afford the title compound (30 mg, 18%). ¹H NMR (400 MHz,DMSO-d6): δ 9.85 (brs, 1H), 9.02 (d, J=6.8 Hz, 1H), 8.33 (dd, J′=8.8 Hz,J″=2.4 Hz, 1H), 7.6 (s, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.43 (t, J=6.0 Hz,1H), 7.3 (t, J=8.4 Hz, 1H), 7.2 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44(brs, 2H), 4.62 (t, J=6.0 Hz, 1H), 4.50 (t, J=5.6 Hz, 1H), 3.9 (brs,4H), 3.81-3.77 (m, 8H), 3.50-3.40 (m, 4H), 3.33-3.20 (m, 2H), 2.21-2.09(m, 2H); ESI-MS: Calculated mass: 625.23; Observed mass: 626.4 [M+H]⁺.

Example 6:N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide

Step 1:4-(2-chloro-8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)morpholine

A 250 mL round bottom flask was charged with4-(6-bromo-2-chloro-8-methoxyquinazolin-4-yl)morpholine (2 g; 0.0056mol), toluene (150 mL), Bis(pinacolato)diboron (1.7 g, 0.0067 mol) andKOAc (1.09 g, 0.011 mol). The reaction mixture was degassed withnitrogen for 15 min. To this mixture was added Pd(dppf)Cl₂.DCM (228 mg,0.00028 mol) and the resulting mixture was degassed again with nitrogenfor 10 min. The reaction mixture was stirred for 3 h at 80° C. Thereaction mixture was filtered through Celite® reagent and the Celite®reagent was washed with toluene (200 mL). The filtrate was evaporatedunder reduced pressure and the residue was washed with hexane (200 mL)to provide the title compound as solid (2 g, 88%). The crude product wasused in the next step without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ 7.8 (s, 1H), 7.36 (s, 1H), 3.93 (s, 3H), 3.87-3.73 (m, 8H),1.32 (s, 12H); ESI-MS: Calculated mass: 405.16; Observed mass: 406.20[M+H]⁺.

Step 2:N-(3-(2-chloro-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide

A 100 mL round bottom flask was charged withN-(3-bromo-2,4-difluorophenyl)propane-1-sulfonamide (0.65 g, 0.002 mol),4-(2-chloro-8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)morpholine(0.83 g, 0.002 mol), DME (20 mL) and 2M aqueous sodium carbonate (0.438g in 2 mL water). The reaction mixture was degassed with nitrogen for 15min. To this mixture was added Pd(dppf)Cl₂.DCM (169 mg, 0.0002 mol) wasadded and the resulting mixture was degassed with nitrogen again for 10min. The reaction mixture was stirred for 2 h at 90° C. The reactionmixture was diluted with water (75 mL) and the resulting mixture wasextracted with ethyl acetate (2×250 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand evaporated under reduced pressure. The crude product was purifiedusing column chromatography (230-400 mesh silica gel; 1% MeOH in DCM) toafford the title compound (200 mg, 18%). ¹H NMR (400 MHz, DMSO-d₆): δ9.70 (brs, 1H), 7.62 (s, 1H), 7.50-7.47 (m, 1H), 7.39 (s, 1H), 7.27 (t,J=8.4 Hz, 1H), 3.93 (s, 3H), 3.80-3.74 (m, 8H), 3.15-3.12 (m, 2H),1.79-1.74 (m, 2H), 0.98 (t, J=7.2 Hz, 3H); ESI-MS: Calculated mass:512.10; Observed mass: 513.20 [M+H]⁺.

Step 3:N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide

A 50 mL round bottom flask was charged withN-(3-(2-chloro-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide(0.1 g, 0.00019 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.063g, 0.00028 mol), sodium carbonate (0.060 g, 0.00056 mol),N,N-dimethylformamide (4 mL) and water (1 mL). The reaction mixture wasdegassed with nitrogen for 10 min. To this mixture Pd(PPh₃)₂Cl₂ (0.013g, 0.000019 mol) was added and the resulting mixture was degassed withnitrogen again for 5 min. The reaction mixture was stirred for 16 h at80° C. The reaction mixture was passed through Celite® reagent, theCelite® reagent was washed with ethyl acetate (50 mL) and the filtratewas evaporated under reduced pressure. The crude product was purifiedusing column chromatography (100-200 mesh silica gel; 3% MeOH in DCM) toafford the title compound (35 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆): δ9.69 (brs, 1H), 9.19 (s, 2H), 7.59 (s, 1H), 7.51-7.45 (m, 1H), 7.33 (s,1H), 7.25 (t, J=8.0 Hz, 1H), 7.19 (brs, 2H), 3.98 (s, 3H), 3.79-3.78 (m,8H), 3.16-3.12 (m, 2H), 1.80-1.74 (m, 2H), 0.99 (t, J=7.2 Hz, 3H);ESI-MS: Calculated mass: 571.18; Observed mass: 570.2 [M−H]⁺.

Example 7:N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

Step 1: 6-chloro-3-nitropicolinonitrile

To a stirred mixture of 2,6-dichloro 3-nitropyridine (10 g, 0.0518 mol)in NMP (100 mL) was added CuCN (9.7 g, 0.1083 mol) and the reactionmixture was heated at 180° C. for 1 h. The reaction mixture was cooledto room temperature and the deep brown mixture was poured into ice-coldwater (300 mL) and filtered through Celite® reagent. The solid wasextracted with 10% methanol in DCM (4×250 mL) and the aqueous layer wasextracted with EtOAc (3×500 mL). The pooled organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedusing column chromatography (100-200 mesh silica gel; 10% EtOAc inhexane) to afford the title compound (3.5 g, 36%). ¹H NMR (400 MHz,DMSO-d₆): δ 8.82 (d, J=8.8 Hz, 1H), 8.17 (d, J=9.6 1H).

Step 2: 3-amino-6-chloropicolinamide

To a stirred mixture of 6-chloro-3-nitropicolinonitrile (3 g, 0.01639mol) in ethanol (40 mL) was added stannous chloride dehydrate (14.7 g,0.06515 mol) at room temperature then the resulting mixture was heatedat 90° C. for 2 h. The reaction mixture was cooled to room temperatureand the ethanol was evaporated under reduced pressure. The residue wasdiluted with ethyl acetate, neutralized with saturated sodiumbicarbonate solution and pH was adjusted to 8-9 with 2M sodium hydroxidesolution. The resulting mixture was passed through Celite® reagent andthe aqueous layer was extracted with ethyl acetate (2×250 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure to affordthe title compound (2.2 g, 78%). H NMR (400 MHz, DMSO-d₆): δ 7.70 (brs,1H), 7.41 (brs, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.0(brs, 2H); ESI-MS: Calculated mass: 171.02; Observed mass: 170.2.[M−H]⁻.

Step 3: 6-chloropyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione

To a stirred mixture of 3-amino-6-chloropicolinamide (2.8 g, 0.0163 mol)in 1,4-dioxane (90 ml) was added triphosgene (4.85 g, 0.0163 mol) atroom temperature. The reaction mixture was heated at 100° C. for 1.5 h.The reaction mixture was cooled to room temperature, water (1 L) wasadded and the solid was collected by filtration. The solid was washedwith ethyl acetate to afford the title compound (2.3 g, 72%). ¹H NMR(400 MHz, DMSO-d₆): δ 11.61 (brs, 1H), 11.36 (brs, 1H), 7.72 (d, J=8.4Hz, 1H), 7.62 (d, J=8.4 Hz, 1H); ESI-MS: Calculated mass: 197.0;Observed mass: 196.10 [M−H]⁻.

Step 4: 2,4,6-trichloropyrido[3,2-d]pyrimidine

To a stirred suspension o6-chloropyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione (2.3 g, 0.0116 mol) inphosphorousoxychloride (30 mL) were added diisipropylethylamine (2.53 g,0.0195 mol) and N,N-dimethylformamide (1 mL) at room temperature. Afterthe addition was complete, the reaction mixture was stirred at 130° C.for 20 h. The excess phosphorousoxychloride was removed by distillationand the residue was azeotroped with toluene. The dark gummy solidobtained was used in the next step without further purification (2.71 gcrude).

Step 5: 4-(2,6-dichloropyrido[3,2-d]pyrimidin-4-yl)morpholine

To a stirred solution of 2,4,6-trichloropyrido[3,2-d]pyrimidine (2.71 g,0.0116 mol) and diisopropylethylamine (4.49 g, 0.0348 mol) indichloromethane (50 mL) morpholine (1.01 g, 0.0116 mol) was addeddropwise at 0° C. The reaction mixture was stirred for 30 min at 0° C.Water (100 mL) was added and the reaction mixture was extracted withdichloromethane (2×250 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and evaporatedunder reduced pressure. The crude product was purified using columnchromatography (100-200 mesh silica gel; 10% EtOAc in hexane) to affordthe title compound (2.2 g, 66%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.12 (d,J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 4.94-4.90 (brs, 4H), 3.78-3.77(m, 4H); ESI-MS: Calculated mass: 284.02; Observed mass: 285.10 [M+H]⁺.

Step 6:N-(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

To a stirred solution of4-(2,6-dichloropyrido[3,2-d]pyrimidin-4-yl)morpholine (0.5 g, 0.00176mol) andN-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(0.6 g, 0.00175 mol) in acetonitrile (20 mL) was added an aqueoussolution of potassium carbonate (486 mg in 2.5 mL water, 0.0035 mol).The reaction mixture was degassed with nitrogen for 15 min. To thismixture was added Pd(PPh₃)₄ (60 mg, 0.000051 mol) and the resultingmixture was degassed with nitrogen again for 10 min. The reactionmixture was stirred at room temperature for 30 min. The solvent wasevaporated under reduced pressure and the residue purified using columnchromatography (100-200 mesh silica gel; 1.5% MeOH in DCM) to afford thetitle compound (350 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.80 (brs,1H), 8.20-8.14 (m, 2H), 7.68 (t, J=6.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.35(t, J=8.0 Hz, 1H), 5.35-4.60 (brm, 2H), 4.40-3.90 (brm, 2H), 3.81-3.79(m, 4H), 3.16-3.13 (m, 2H), 1.80-1.72 (m, 2H), 0.98 (t, J=8.0 Hz, 3H);ESI-MS: Calculated mass: 465.10; Observed mass: 466.20 [M+H]⁺.

Step 7:N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

To a stirred solution ofN-(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide(0.175 g, 0.000376 mol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.20g, 0.000936 mol) in DMF (8 mL) was added an aqueous solution of sodiumcarbonate (0.159 g in 2 mL water, 0.0015 mol) at room temperature. Thereaction mixture was degassed with nitrogen for 15 min. To this mixturewas added Pd(PPh₃)₂Cl₂ (26 mg, 0.000037 mol) and the resulting mixturewas degassed with nitrogen for 10 min. The reaction mixture was heatedat 80° C. for 1.5 h. The reaction mixture was passed through Celite®reagent and the Celite® reagent was washed with ethyl acetate (100 mL).The organic layer was washed with water (2×50 mL), followed by brinesolution, dried over anhydrous sodium sulfate and filtered. The solventwas evaporated under reduced pressure and the crude product was purifiedusing column chromatography (neutral alumina; 7% MeOH in DCM) to affordthe title compound (6 mg, 3%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.80 (brs,1H), 9.18 (brs, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H),7.69 (t, J=6.0 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H),7.19 (brs, 2H), 4.65-4.40 (brm, 4H), 3.83 (brs, 4H), 3.20-3.14 (m, 2H),1.78-1.76 (m, 2H), 0.99 (t, J=6.4 Hz, 3H); ESI-MS: Calculated mass:524.18; Observed mass: 523.4 [M−H]⁺.

Example 8:N-(3-(2-(6-aminopyridin-3-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

Step 1: (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide

A three neck 2 L round bottom flask was charged with chloral hydrate(39.9 g, 0.241 mol), anhydrous sodium sulfate (312.2 g, 1.75 mol) andwater (880 mL). The solution was stirred and heated at 40° C. until themixture became clear. To this mixture was added o-toluidine (23.4 g,0.219 mol dissolved in 135 mL of water and 19 mL of hydrochloric acid)and hydroxylamine hydrochloride (50.2 g, 0.723 mol). The resultingsolution was heated at 100° C. for 1.5 h and then cooled to roomtemperature. The product precipitated out of solution after standing for16 h at room temperature. The solid was collected by filtration anddried to afford the title compound (27 g, 69%). ¹H NMR (400 MHz,DMSO-d₆): δ 12.17 (s, 1H), 9.48 (brs, 1H), 7.67 (s, 1H), 7.47 (d, J=7.60Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.20-7.09 (m, 2H), 2.20 (s, 3H);ESI-MS: Calculated mass: 178.07; Observed mass: 177.30 [M−H]⁻.

Step 2: 7-methylindoline-2,3-dione

To a preheated (50° C.) solution of concentrated sulfuric acid (93.39mL) under rapid stirring was added slowly2-(hydroxyimino)-N-(o-tolyl)acetamide (27 g, 0.151 mol), keeping thetemperature of the reaction between 60° C. and 70° C. Once the additionwas complete, the reaction mixture was heated to 80° C. and stirred for20 min. The reaction mixture was then allowed to cool to roomtemperature and poured over crushed ice (800 g). A crude rust coloredprecipitate was formed which was extracted with ethyl acetate (2×300 mL)followed by 10% methanol in dichloromethane. The combined organic layerswere dried over sodium sulfate, filtered and the filtrate was evaporatedunder reduced pressure to afford the title compound (7 g, 28%) as anorange solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 7.42 (d, J=7.2Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 6.98 (t, J=7.6 Hz, 1H), 2.19 (s, 3H);ESI-MS: Calculated mass: 161.05; Observed mass: 160.10 [M−H]⁻.

Step 3: 5-bromo-7-methylindoline-2,3-dione

To a stirred mixture of 7-methylindoline-2,3-dione (7 g, 0.043 mol) inchloroform (700 mL) was added a solution of bromine (2.8 mL, 0.053 mol)in chloroform (100 mL) dropwise over 15 min at room temperature. Thereaction mixture was heated at 80° C. for 24 h and then cooled to 0° C.,which resulted in precipitation of the product as a red solid. The solidwas collected by suction filtration and dried under vacuum to afford thetitle compound (8 g, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.20 (s, 1H),7.64 (d, J=1.2 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 2.18 (s, 3H); ESI-MS:Calculated mass: 238.96; Observed mass: 238.30 [M−H]⁻.

Step 4: 2-amino-5-bromo-3-methylbenzoic acid

A mixture of 5-bromo-7-methylindoline-2,3-dione (8 g, 0.033 mol), sodiumchloride (4.5 g, 0.09 mol) and sodium hydroxide (3.6 g, 0.09 mol) wasdissolved in water (96 mL) with stirring to give a yellow solution. Thereaction mixture was cooled to 0° C. and to this mixture was addedslowly a solution of 30% hydrogen peroxide (7 mL) and sodium hydroxide(6.27 g) in 83 mL of water. The reaction mixture was stirred for another1.5 h at 0° C. and then quenched with glacial acetic acid to give a tanprecipitate. The solid was filtered, washed thoroughly with cold waterand dried under vacuum to afford the title compound (5.8 g, 75%). ¹H NMR(400 MHz, DMSO-d₆): δ 7.69 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 2.0 (s, 3H);ESI-MS: Calculated mass: 228.97; Observed mass: 228.10 [M−H]⁻.

Step 5: 6-bromo-8-methylquinazoline-2,4(1H,3H)-dione

A mixture of urea (15.28 g, 0.254 mol) and2-amino-5-bromo-3-methylbenzoic acid (7.6 g, 0.031 mol) was heated at180° C. for 4 h. After confirming the completion of reaction by TLC, thereaction mixture was allowed to cool to 80° C. and water (200 mL) wasadded. The aqueous reaction mixture was stirred at 80° C. for 30 min andthe precipitate was collected by filtration. The solid compound (8.4 g,little impure) obtained was taken into the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆): δ 7.82 (d, J=2.0 Hz, 1H), 7.68(d, J=1.6 Hz, 1H), 2.33 (s, 3H); ESI-MS: Calculated mass: 253.97;Observed mass: 255.20 [M+H]⁺.

Step 6: 6-bromo-2,4-dichloro-8-methylquinazoline

To a stirred suspension of 6-bromo-8-methylquinazoline-2,4(1H,3H)-dione(9.4 g, 0.037 mol) in phosphorus oxychloride (84 mL) were added dropwisediisoproylethylamine (5.14 mL, 0.037 mol) and N,N-dimethylformamide (1.3mL) at room temperature. The reaction mixture was heated at 130° C. for24 h. Excess phosphorusoxychloride was removed by distillation and theresidue was azeotroped with toluene. The reaction mixture was cooled toroom temperature, poured into water (150 mL) and stirred for 30 min. Thesolid that separated was collected by filtration and dried under vacuumto afford the title compound (8.8 g, 92%). H NMR (400 MHz, DMSO-d₆): δ8.28 (s, 1H), 8.22 (s, 1H), 2.64 (s, 3H).

Step 7: 4-(6-bromo-2-chloro-8-methylquinazolin-4-yl)morpholine

To a stirred solution of 6-bromo-2,4-dichloro-8-methylquinazoline (8.8g, 0.030 mol) in dichloromethane (300 mL) were addeddiisopropylethylamine (10 mL, 0.06 mol) and morpholine (2.7 mL, 0.03mol) at 0° C. then the reaction mixture was stirred for 30 min at 0° C.Water (100 mL) was added and the reaction mixture was filtered throughCelite® reagent, and the Celite® reagent was washed with dichloromethane(200 mL). The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×200 mL). The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The crude product was purifiedusing column chromatography (60-120 mesh silica gel; 20% EtOAc inhexane) to afford the title compound as a yellow solid (9 g, 87%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.97 (d, J=2.0 Hz, 1H), 7.88 (d, J=0.8 Hz,1H), 3.83-3.73 (m, 8H), 2.53 (s, 3H).

Step 8:N-(3-(2-chloro-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

A 50 mL round bottom flask was charged with4-(6-bromo-2-chloro-8-methylquinazolin-4-yl)morpholine (0.3 g, 0.000879mol),N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(0.36 g, 0.00105 mol), sodium carbonate (0.184 g in 2 mL water, 0.00174mol) and DMF (8 mL). The reaction mixture was degassed with nitrogen for15 min. To this mixture was added Pd(PPh₃)₂Cl₂ (60 mg, 0.0000879 mol)and the resulting mixture was degassed with nitrogen again for 10 min.The reaction mixture was stirred for 12 h at 80° C. The reaction mixturewas diluted with ethyl acetate (40 mL), filtered through Celite®reagent, and the Celite® reagent was washed with ethyl acetate (100 mL).The organic layer was washed with cold water (50 mL), dried overanhydrous sodium sulfate, filtered and evaporated under reducedpressure. The crude product was purified using column chromatography(230-400 mesh silica gel; 1% MeOH in DCM) to afford the title compound(200 mg, 47%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.73 (brs, 1H), 8.14 (s,1H), 8.11 (s, 1H), 7.49-7.42 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 3.85-3.76(m, 8H), 3.17-3.11 (m, 2H), 2.63 (s, 3H), 1.82-1.72 (m, 2H), 0.85 (t,J=6.4 Hz, 3H); ESI-MS: Calculated mass: 478.12; Observed mass: 479.3[M+H]⁺.

Step 9:N-(3-(2-(6-aminopyridin-3-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

A 50 mL round bottom flask was charged withN-(3-(2-chloro-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide(0.2 g, 0.00040 mol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.18 g,0.0008 mol), aqueous sodium carbonate (0.169 g in 2 mL water, 0.0016mol) and DMF (8 mL). The reaction mixture was degassed with nitrogen for15 min. To this mixture was added Pd(PPh₃)₂Cl₂ (28 mg, 0.00004 mol) andthe resulting mixture was degassed with nitrogen for 10 min. Thereaction mixture was stirred at 80° C. for 12 h. The reaction mixturewas filtered through Celite® reagent and the Celite® reagent was washedwith ethyl acetate (100 mL). The organic layer was washed with coldwater (2×50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purifiedusing preparative HPLC to afford the title compound (13 mg, 6%). ¹H NMR(400 MHz, DMSO-d₆): δ 9.70 (brs, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.42 (dd,J=8.8 Hz, J′=1.6 Hz, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.44 (t, J=8.4 Hz,2H), 7.29 (t, J=7.6 Hz, 1H), 6.55 (d, J=8.8 Hz, 1H), 6.45 (brs, 2H),3.81-3.79 (m, 8H), 3.14 (t, J=7.2 Hz, 2H), 2.69 (s, 3H), 1.80-1.74 (m,2H), 1.02 (t, J=6.4 Hz, 3H); ESI-MS: Calculated mass: 536.2; Observedmass: 537.1 [M+H]⁺.

Example 9:N-(3-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

Step 1:4-(6-bromo-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxyquinazolin-4-yl)morpholine

To a stirred mixture of4-(6-bromo-2-chloro-8-methoxyquinazolin-4-yl)morpholine (300 mg, 0.00084mol) and potassium carbonate (348 mg, 0.00251 mol) inN,N-dimethylformamide (10 ml) was added2-(difluoromethyl)-1H-benzo[d]imidazole (169 mg, 0.001 mol) atroomtemperature. The reaction mixture was heated at 80° C. for 16 h. Thereaction mixture was added to ice-cold water (100 mL). The solidseparated was collected by filtration, washed with 5% EtOAc in hexaneand dried under vacuum to afford the title compound as white solid (230mg, 56%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.67 (d, J=8.40 Hz, 1H), 7.96 (t,J=53.2 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.54 (d,J=2.0 Hz, 1H), 7.53-7.43 (m, 2H), 4.05 (s, 3H), 3.94-3.83 (m, 8H);ESI-MS: Calculated mass: 489.06; Observed mass: 490.20 [M+H]⁺.

Step 2:N-(3-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide

A 50 mL round bottom flask, was charged with4-(6-bromo-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxyquinazolin-4-yl)morpholine(0.12 g, 0.000245 mol),N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(0.126 g, 0.000367 mol), sodium carbonate (0.077 g, 0.000726 mol) and 10mL of DMF and water mixture (4:1). The reaction mixture was degassedwith nitrogen for 15 min. To this mixture was added Pd(PPh₃)₂Cl₂ (17 mg,0.00002 mol) and the resulting mixture was degassed with nitrogen againfor 10 min. The reaction mixture was heated at 80° C. for 2 hours. Water(50 mL) was added and the resulting mixture was extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure. The crude product was purified using columnchromatography (230-400 mesh silica gel; 2% MeOH in DCM) to afford thetitle compound (46 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.75 (brs,1H), 8.72 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.59(s, 1H), 7.57-7.44 (m, 5H), 7.34 (t, J=7.6 Hz, 1H), 4.09 (s, 3H),3.93-3.85 (m, 8H), 3.17 (t, J=7.6 Hz, 2H), 1.82-1.76 (m, 2H), 1.09 (t,J=7.6 Hz, 3H); ESI-MS: Calculated mass: 626.19; Observed mass: 625.4[M−H]⁻.

Example 10 (TBDMS Deprotection):N-(2-fluoro-3-(2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide

To a stirred solution ofN-(3-(2-(2-(tert-butyldimethylsilyl)oxy)methyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide(0.2 g, 0.000277 mol) in dichloromethane (10 mL) was addedtetra-n-butylammonium fluoride (1M in solution in THF, 0.18 g, 0.000689mol) at room temperature and the stirring was continued for 16 h. Thereaction mixture was diluted with water (50 mL), neutralized withsaturated sodium bicarbonate solution and extracted with dichloromethane(2×100 mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude product waspurified using preparative HPLC to afford the title compound (17 mg,10%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.75 (s, 1H), 8.45 (d, J=8.4 Hz, 1H),7.73 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 7.55-7.51 (m, 2H), 7.47 (t, J=7.6Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.35-7.30 (m, 2H), 6.01 (t, J=6.4 Hz,1H), 4.96 (d, J=7.2 Hz, 2H), 4.06 (s, 3H), 3.96-3.95 (m, 4H), 3.88-3.87(m, 4H), 3.15 (t, J=7.2 Hz, 2H), 1.79-1.77 (m, 2H), 1.0 (t, J=7.6 Hz,3H); ESI-MS: Calculated mass: 606.2; Observed mass: 605.30 [M−H]⁻.

Example 11:N-(3-(2-(2-aminopyrimidin-5-yl)-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide

Step 1: 2-Amino-5-bromo-4-methoxybenzoic acid

To a stirred suspension of 2-amino-4-methoxybenzoic acid (5 g, 0.029mol) in acetic acid (100 mL) was added bromine (1.23 mL, 0.023 mol)dropwise at 0° C. The reaction mixture was stirred at room temperaturefor 8 h. The separated solid was filtered, washed with water (30 mL) anddried under vacuum to afford the product as white solid (6.3 g, 86%). Asper the LC-MS data this solid contains 14% of starting material, 22% ofdibromo byproduct and 61% of desired compound. ¹H NMR (400 MHz,DMSO-d₆): δ 7.76 (s, 1H), 6.42 (s, 1H), 3.72 (s, 3H); ESI-MS: Calculatedmass: 244.97; Observed mass LC-MS: 246.0 [M+H]⁺ RT: 2.07 min.

Step 2: Methyl 2-amino-5-bromo-4-methoxybenzoate

To a stirred suspension of 2-amino-5-bromo-4-methoxybenzoic acid (6.3 g,0.025 mol) and potassium carbonate (7.06 g, 0.051 mol) in N,N-dimethylformamide (63 mL) was added methyl iodide (5.45 g, 0.038 mol) dropwiseat 0° C. After the addition was complete, the reaction mixture wasstirred at room temperature for 1 h. The mixture was poured into icecold water (500 mL) and extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with water (100 mL) followed bybrine solution, dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the crude product waspurified using column chromatography (100-200 mesh silica gel, 20% EtOAcin hexane) to afford the title compound as white solid (5.5 g, 83%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.78 (s, 1H), 6.85 (brs, 2H), 6.44(s, 1H), 3.80 (s, 3H), 3.75 (s, 3H). ESI-MS: Calculated mass: 258.98;Observed mass: 258.3 [M−H]⁻.

Step 3: 6-Bromo-7-methoxyquinazoline-2,4(1H,3H)-dione

To a stirred suspension of methyl 2-amino-5-bromo-4-methoxybenzoate (5.5g, 0.021 mol) in acetic acid (25 mL) was added 0.1 M aqueous solution ofpotassium cyanate (7.49 g, 0.10 mol) dropwise at room temperature. Thereaction mixture was stirred at 50° C. for 24 h. The solid separated wasfiltered, washed with water (20 mL) followed by 10% EtOAc in hexane (50mL) and dried under vacuum to afford the corresponding urea.

To the stirred suspension of the above urea in methanol (20 mL) wasadded 2N sodium hydroxide (10 mL). The reaction mixture was stirred at90° C. for 1 h. The mixture was cooled to room temperature, acidifiedwith 3M hydrochloric acid to pH 3. The solid obtained was filtered anddried under vacuum to afford the title compound as white solid (3.5 g,61% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.29 (s, 1H), 11.18 (s, 1H),7.94 (s, 1H), 6.74 (s, 1H), 3.90 (s, 3H).

Step 4: 6-Bromo-2,4-dichloro-7-methoxyquinazoline

To a stirred suspension of 6-bromo-7-methoxyquinazoline-2,4(1H,3H)-dione(1.7 g, 0.006 mol) in phosphorousoxychloride (25.5 mL; POCl₃) were addeddiisopropyl ethylamine (1.7 mL) and N,N-dimethylformamide (0.85 mL)sequentially. The reaction mixture was maintained at 130° C. for 8 h.POCl₃ was removed by distillation and the crude residue was azeotropedtwice with toluene to afford the title compound (1.7 g, crude). Thiscompound was used in the next step without any further purification.

Step 5:4-(6-Bromo-2-chloro-7-methoxy-4,4a-dihydroquinazolin-4-yl)morpholine

To a stirred solution of 6-bromo-2,4-dichloro-7-methoxyquinazoline (1.7g, 0.005 mol) and diisopropylethylamine (3.62 mL, 0.022 mol) indichloromethane (100 mL) was added morpholine (0.48 mL, 0.005 mol)slowly at 0° C. After the addition was complete, the reaction mixturewas stirred at 0° C. for 30 min. The reaction mixture was diluted withwater (50 mL) and extracted with dichloromethane (2×200 mL). The organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified using column chromatography (100-200 mesh silica gel, 30% EtOAcin hexane) to afford the title compound as off white solid (850 mg, 43%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (s, 1H), 7.29 (s, 1H), 3.99(s, 3H), 3.83-3.74 (m, 8H); ESI-MS: Calculated mass: 356.99; Observedmass: 358.20 [M+H]⁺.

Step 6:N-(3-(2-Chloro-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide

To a 100 mL round bottom flask were added4-(6-bromo-2-chloro-7-methoxy-4,4a-dihydroquinazolin-4-yl)morpholine (1g, 0.0027 mol), N,N-dimethylformamide (20 mL), water (5 mL),3-fluoro-N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide(2.01 g, 0.0055 mol) and sodium carbonate (589 mg, 0.005 mol). Thereaction mixture was degassed with nitrogen for 10 min. To this mixturewas added Pd(PPh₃)₂Cl₂ (195 mg, 0.0002 mol) and the resulting mixturewas degassed again for 5 min. The reaction mixture was stirred at 80° C.for 1 h. Water (50 mL) was added and the reaction mixture was extractedwith ethyl acetate (2×100 mL). The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified using columnchromatography (100-200 mesh silica gel, 30% EtOAc in hexane) to affordthe title compound (800 mg, 57% yield). ¹H NMR (400 MHz, DMSO-d₆): δ9.83 (brs, 1H), 7.93 (s, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.34 (t, J=6.4 Hz,1H), 7.30 (s, 1H), 7.28-7.24 (m, 1H), 4.61 (t, J=6.0 Hz, 1H), 4.49 (t,J=6.0 Hz, 1H), 3.93 (s, 3H), 3.88-3.72 (m, 8H), 3.24-3.19 (m, 2H),2.18-2.01 (m, 2H); ESI-MS: Calculated mass: 512.1; Observed mass: 511.3[M−H]⁻.

Step 7:N-(3-(2-(2-Aminopyrimidin-5-yl)-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide

To a 100 mL round bottom flask, were addedN-(3-(2-chloro-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide(200 mg, 0.0003 mol), N,N-dimethylformamide (10 mL), water (2 mL),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (172mg, 0.0007 mol) and sodium carbonate (164 mg, 0.0015 mol). The reactionmixture was degassed with nitrogen for 10 min. To this mixture was addedPd(PPh₃)₂Cl₂ (27 mg, 0.00003 mol) and the resulting mixture was degassedagain for 5 min. The reaction mixture was stirred at 80 for 1 h. Water(50 mL) was added and the reaction mixture was extracted with 10% MeOHin EtOAc (2×50 mL). The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified using column chromatography(100-200 mesh silica gel, 4% MeOH in DCM) to get the desired product in85% purity. This product was again purified using preparative HPLC toafford the title compound as an off white solid (62 mg, 28% yield). ¹HNMR (400 MHz, DMSO-d₆): δ9.84 (s, 1H), 9.20 (s, 2H), 7.81 (s, 1H), 7.44(t, J=7.6 Hz, 1H), 7.37-7.34 (i, 2H), 7.27 (t, J=8.0 Hz, 1H), 7.19 (brs,2H), 4.61 (t, J=6.0 Hz, 1H), 4.49 (t, J=6.0 Hz, 1H), 3.91 (s, 3H),3.78-3.68 (m, 8H), 3.23-3.22 (m, 2H), 2.17-2.10 (n, 2H); Calculatedmass: 571.18; Observed mass: 572.3 [M+H]⁺. ESI-MS characterization datafor Examples 1-120 are provided in Table 2.

TABLE 2 Mass (ESI- Ex Structure Structure Name MS) Scheme 1

2,6-difluoro-N-(2-fluoro-3-(8- methoxy-2-(4-(3- methylureido)phenyl)-4-morpholinoquinazolin-6- yl)phenyl)benzenesulfonamide 679.30 [M + H]⁺ 9 2

N-(3-(2-(1H-indazol-4-yl)-8- methoxy-4- morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1- sulfonamide 577.40 [M + H]⁺ 9 3

N-(3-(2-(6-((2- aminoethyl)amino)pyridin-3-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 596.20[M + H]⁺ 9 4

N-(3-(2-(6-aminopyridin-3-yl)-8- (2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 583.10[M + H]⁺ 10 5

N-(3-(2-(6-aminopyridin-3-yl)- 4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3- fluoropropane-1-sulfonamide 626.40 [M + H]⁺ 11 6

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)propane-1- sulfonamide570.20 [M − H]⁻ 12 7

N-(3-(2-(2-aminopyrimidin-5-yl)- 4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 523.40 [M − H]⁻13 8

N-(3-(2-(6-aminopyridin-3-yl)-8- methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1- sulfonamide 537.10 [M + H]⁺ 14 9

N-(3-(2-(2-(difluoromethyl)-1H- benzo[d]imidazol-1-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 625.40[M − H]⁻ 15 10

N-(2-fluoro-3-(2-(2- (hydroxymethyl)-1H- benzo[d]imidazol-1-yl)-8-methoxy-4- morpholinoquinazolin-6- yl)phenyl)propane- 1-sulfonamide605.30 [M − H]⁻ 15 11

N-(3-(2-(2-aminopyrimidin-5-yl)- 7-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 572.30 [M + H]⁺ 16 12

2,6-difluoro-N-(2-fluoro-3-(2-(4- (3-(2- hydroxyethyl)ureido)phenyl)-8-methoxy-4- morpholinoquinazolin-6- yl)phenyl)benzenesulfonamide 707.50[M − H]⁻ 9 13

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2,6-difluorobenzenesulfonamide 622.20 [M − H]⁻ 9 14

N-(2-fluoro-3-(8-methoxy-2-(4- (3-methylureido)phenyl)-4-morpholinoquinazolin-6- yl)phenyl)propane- 1-sulfonamide 609.50 [M + H]⁺9 15

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 554.20[M + H]⁺ 9 16

2,6-difluoro-N-(2-fluoro-3-(8- methoxy-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)quinazolin-6- yl)phenyl)benzenesulfonamide647.30 [M + H]⁺ 9 17

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 551.30[M − H]⁻ 9 18

N-(3-(2-(6-amino-2- fluoropyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 571.40[M + H]⁺ 9 19

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2,6-difluorobenzenesulfonamide 623.20 [M + H]⁺ 9 20

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2-methylpropane-1-sulfonamide 568.30 [M + H]⁺ 9 21

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)ethanesulfonamide 538.30 [M −H]⁻ 9 22

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2,5-difluorobenzenesulfonamide 622.30 [M − H]⁻ 9 23

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)butane-1- sulfonamide 566.30[M − H]⁻ 9 24

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2,4-difluorobenzenesulfonamide 622.30 [M − H]⁻ 9 25

N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 621.30[M + H]⁺ 9 26

N-(3-(2-(6-amino-5- methylpyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide567.30 [M + H]⁺ 9 27

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 570.40 [M − H]⁻ 9 28

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2,5-difluorobenzenesulfonamide 623.40 [M + H]⁺ 9 29

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2- fluorobenzenesulfonamide603.30 [M − H]⁻ 9 30

N-(3-(2-(6-aminopyridin-3-yl-8- methoxy-4- morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1- sulfonamide 571.30 [M + H]⁺ 9 31

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide 605.20 [M − H]⁻ 9 32

3-fluoro-N-(2-fluoro-3-(8- methoxy-2-(4-(3- methylureido)phenyl)-4-morpholinoquinazolin-6- yl)phenyl)propane-1-sulfonamide 627.40 [M + H]⁺9 33

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-2- sulfonamide 551.20[M − H]⁻ 9 34

N-(2-fluoro-3-(8-methoxy-4- morpholino-2-(4-(3-(pyridin-4-yl)ureido)phenyl)quinazolin-6- yl)phenyl)propane-1-sulfonamide 672.20[M + H]⁺ 9 35

N-(3-(2-(2-amino-4- methylpyrimidin-5-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 586.30 [M + H]⁺ 9 36

N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 639.0 [M + H]⁺ 9 37

N-(3-(2-(1H-indazol-4-yl)-8- methoxy-4- morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1- sulfonamide 595.30 [M + H]⁺ 9 38

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)thiophene-2- sulfonamide593.20 [M + H]⁺ 9 39

3-fluoro-N-(2-fluoro-3-(8- methoxy-2-(6-(3-methylureido)pyridin-3-yl)-4- morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide 628.30 [M + H]⁺ 9 40

3-fluoro-N-(2-fluoro-3-(8- methoxy-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)quinazolin-6-yl)phenyl)propane-1-sulfonamide 595.30 [M + H]⁺ 9 41

(S)-N-(3-(2-(6-aminopyridin-3- yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 586.20 [M + H]⁺ 9 42

(R)-N-(3-(2-(6-aminopyridin-3- yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 585.10 [M + H]⁺ 9 43

(R)-N-(3-(2-(2-aminopyrimidin- 5-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 586.40 [M + H] 9 44

(R)-3-fluoro-N-(2-fluoro-3-(8- methoxy-4-(3- methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)quinazolin-6-yl)phenyl)propane-1-sulfonamide 607.40 [M − H]⁻ 9 45

(S)-N-(3-(2-(2-aminopyrimidin-5- yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 586.20 [M + H]⁺ 9 46

N-(3-(2-(6-aminopyridin-3-yl)-4- morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1- sulfonamide 541.20 [M + H]⁺ 9 47

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-2- fluorobenzenesulfonamide604.30 [M − H]⁻ 9 48

N-(3-(2-(6-amino-5- chloropyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 587.40[M + H]⁺ 9 49

3-fluoro-N-(2-fluoro-3-(8- methoxy-4-morpholino-2-(6-(propylamino)pyridin-3- yl)quinazolin-6- yl)phenyl)propane-1-sulfonamide613.20 [M + H]⁺ 9 50

3-fluoro-N-(2-fluoro-3(8- methoxy-2-(6- (methylamino)pyridin-3-yl)-4-morpholinoquinazolin-6- yl)phenyl)propane-1-sulfonamide 585.30 [M + H]⁺9 51

3-fluoro-N-(2-fluoro-3-(8- methoxy-2-(2- (methylamino)pyrimidin-5-yl)-4-morpholinoquinazolin-6- yl)phenyl)propane-1-sulfonamide 586.10 [M + H]⁺9 52

N-(3-(2-(6-aminopyridin-3-yl)-8- ethoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3- fluoropropane-1-sulfonamide 585.30 [M + H]⁺ 1053

N-(3-(2-(6-aminopyridin-3-yl)-8- (cyclopentyloxy)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 625.40 [M + H]⁺ 10 54

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-ethoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 584.30 [M − H]⁻ 10 55

N-(3-(2-(6-aminopyridin-3-yl)-8- isopropoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 599.30 [M + H]⁺ 10 56

N-(3-(8-(2-aminoethoxy)-2-(6- aminopyridin-3-yl)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1-sulfonamide 600.30 [M + H]⁺ 10 57

N-(3-(2-(6-aminopyridin-3-yl)-8- (cyclopropylmethoxy)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1-sulfonamide 611.40 [M + H]⁺ 10 58

N-(3-(2-(6-aminopyridin-3-yl)-8- (2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1-sulfonamide 601.40 [M + H]⁺ 10 59

2-((2-(6-aminopyridin-3-yl)-6-(2- fluoro-3-(3- fluoropropylsulfonamido)phenyl)- 4-morpholinoquinazolin-8- yl)oxy)acetic acid 2,2,2-trifluoroacetate 615.30 [M + H]⁺ 10 60

2-((2-(6-aminopyridin-3-yl)-6-(2- fluoro-3-(3- fluoropropylsulfonamido)phenyl)- 4-morpholinoquinazolin-8- yl)oxy)acetamide 614.30 [M + H]⁺ 1061

(R)-N-(3-(8-ethoxy-4-(3- methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-5- yl)quinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 623.50 [M + H]⁺ 10 62

(R)-N-(3-(2-(6-aminopyridin-3- yl)-8-(cyclopentyloxy)-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 639.40 [M + H]⁺ 10 63

(R)-N-(3-(2-(6-aminopyridin-3- yl)-8-isopropoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 613.10 [M + H]⁺ 10 64

(R)-N-(3-(2-(2-aminopyrimidin- 5-yl)-8-isopropoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 614.40 [M + H]⁺ 10 65

(S)-N-(3-(2-(6-aminopyridin-3- yl)-8-ethoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 599.50 [M + H]⁺ 10 66

(S)-N-(3-(2-(2-aminopyrimidin-5- yl)-8-ethoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 600.30 [M + H]⁺ 10 67

N-(3-(2-(6-aminopyridin-3-yl)-8- (2-methoxyethoxy)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 615.30 [M + H]⁺ 10 68

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-(2-methoxyethoxy)-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1-sulfonamide 616.40 [M + H]⁺ 10 69

N-(3-(2-(2-aminopyrimidin-5-yl)- 4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3- fluoropropane-1-sulfonamide 627.30 [M + H]⁺ 11 70

N-(3-(2-(6-aminopyridin-3-yl)-4- morpholino-8-(pyrrolidin-1-yl)quinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide610.40 [M + H]⁺ 11 71

N-(3-(2-(2-aminopyrimidin-5-yl)- 4-morpholino-8-(pyrrolidin-1-yl)quinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide611.50 [M + H]⁺ 11 72

(R)-N-(3-(2-(6-aminopyridin-3- yl)-4-(3-methylmorpholino)-8-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1-sulfonamide 640.30 [M + H]⁺ 11 73

(R)-N-(3-(2-(2-aminopyrimidin- 5-yl)-4-(3-methylmorpholino)-8-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3- fluoropropane-1-sulfonamide 641.20 [M + H]⁺ 11 74

(R)-N-(3-(2-(6-aminopyridin-3- yl)-4-(3-methylmorpholino)-8-(pyrrolidin-1-yl)quinazolin-6-yl)- 2-fluorophenyl)-3- fluoropropane-1-sulfonamide 624.50 [M + H]⁺ 11 75

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)propane-1- sulfonamide571.40 [M + H]⁺ 12 76

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)-2,6-difluorobenzenesulfonamide 640.20 [M − H]⁻ 12 77

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)-2,6-difluorobenzenesulfonamide 641.10 [M + H]⁺ 12 78

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)-2,5-difluorobenzenesulfonamide 639.40 [M − H]⁻ 12 79

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)-3- fluoropropane-1-sulfonamide 589.40 [M + H]⁺ 12 80

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-4- chloro-2-fluorophenyl) propane-1-sulfonamide 585.20 [M − H]⁻ 12 81

N-(3-(2-(1H-indazol-4-yl)-8- methoxy-4- morpholinoquinazolin- 6-yl)-2,4-difluorophenyl)-3- fluoropropane- 1-sulfonamide 613.10 [M + H]⁺ 12 82

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methoxy-4- morpholinoquinazolin-6-yl)-2,4- difluorophenyl)- 3-fluoropropane- 1-sulfonamide 588.30 [M −H]⁻ 12 83

N-(2,4-difluoro-3-(8-methoxy-4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6- yl)phenyl)-3-fluoropropane-1- sulfonamide613.10 [M + H]⁺ 12 84

N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-2,4- difluorophenyl)-3-fluoropropane-1-sulfonamide 657.30 [M + H]⁺ 12 85

N-(3-(2-(6-aminopyridin-3-yl)-8- methoxy-4-morpholinoquinazolin-6-yl)-4- chloro-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 603.30 [M − H]⁻ 12 86

N-(3-(2-(6-aminopyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)propane-1- sulfonamide 524.20 [M + H]⁺13 87

N-(3-(2-(2-aminopyrimidin-5-yl)- 4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 541.40[M − H]⁻ 13 88

N-(3-(2-(6-aminopyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 540.30[M − H]⁻ 13 89

N-(3-(2-(1H-indazol-4-yl)-4- morpholinopyrido[3,2- d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1- sulfonamide 564.30 [M − H]⁻ 13 90

N-(3-(2-(6-amino-5- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 556.40[M + H]⁺ 13 91

3-fluoro-N-(2-fluoro-3-(4- morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2- d]pyrimidin-6- yl)phenyl)propane-1-sulfonamide 564.40 [M − H]⁻ 13 92

N-(3-(2-(6-aminopyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-2,5- difluorobenzenesulfonamide594.30 [M + H]⁺ 13 93

N-(3-(2-(2-aminopyrimidin-5-yl)- 4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-2,5- difluorobenzenesulfonamide595.30 [M + H]⁺ 13 94

N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 610.30 [M + H]⁺ 13 95

N-(3-(2-(6-aminopyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-2,6- difluorobenzenesulfonamide594.30 [M + H]⁺ 13 96

(R)-N-(3-(2-(6-aminopyridin-3- yl)-4-(3- methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)- 3-fluoropropane-1- sulfonamide556.40 [M + H]⁺ 13 97

(R)-N-(3-(2-(2-aminopyrimidin- methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)- 3-fluoropropane-1- sulfonamide557.30 [M + H]⁺ 13 98

N-(3-(2-(2-aminopyrimidin-5-yl)- 4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-2,6- difluorobenzenesulfonamide595.30 [M + H]⁺ 13 99

3-fluoro-N-(2-fluoro-3-(2-(6-((2- hydroxyethyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6- yl)phenyl)propane-1-sulfonamide 586.20 [M + H]⁺ 13 100

N-(3-(2-(2-amino-4- (trifluoromethyl)pyrimidin-5-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 611.40 [M + H]⁺ 13 101

N-(3-(2-(6-amino-4- methylpyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide554.50 [M − H]⁻ 13 102

N-(3-(2-(6-amino-4- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide560.20 [M + H]⁺ 13 103

N-(3-(2-(6-amino-5- chloropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide576.20 [M + H]⁺ 13 104

N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-2,5-difluorobenzenesulfonamide 660.30 [M − H]⁻ 13 105

N-(3-(2-(6-amino-5- fluoropyridin-3-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide560.20 [M + H]⁺ 13 106

N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-2,6-difluorobenzenesulfonamide 662.30 [M + H]⁺ 13 107

(R)-N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 624.30 [M + H]⁺ 13 108

(S)-N-(3-(2-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 624.50 [M + H]⁺ 13 109

N-(3-(2-(2-amino-4- methylpyrimidin-5-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide557.30 [M + H]⁺ 13 110

3-fluoro-N-(2-fluoro-3-(2-(2-((3- hydroxypropyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6- yl)phenyl)propane-1-sulfonamide 601.30 [M + H]⁺ 13 111

3-fluoro-N-(2-fluoro-3-(2-(6-((3- hydroxypropyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6- yl)phenyl)propane-1-sulfonamide 598.40 [M − H]⁻ 13 112

3-fluoro-N-(2-fluoro-3-(4- morpholino-2-(2- (propylamino)pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-6- yl)phenyl)propane- 1-sulfonamide 585.10[M + H]⁺ 13 113

3-fluoro-N-(2-fluoro-3-(2-(6- (methylamino)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl) phenyl)propane- 1-sulfonamide556.0 [M + H]⁺ 13 114

3-fluoro-N-(2-fluoro-3-(2-(6- (isopropylamino)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl)phenyl)propane- 1-sulfonamide584.20 [M + H]⁺ 13 115

3-fluoro-N-(2-fluoro-3-(4- morpholino-2-(6- (propylamino)pyridin-3-yl)pyrido[3,2-d]pyrimidin-6- yl)phenyl)propane-1-sulfonamide 584.40 [M +H]⁺ 13 116

N-(3-(2-(2-aminopyrimidin-5-yl)- 8-methyl-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 556.40 [M + H]⁺ 14 117

N-(3-(2-(6-aminopyridin-3-yl)-8- methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3- fluoropropane-1-sulfonamide 555.30 [M + H]⁺ 14118

N-(3-(2-(1H-indazol-4-yl)-8- methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3- fluoropropane-1-sulfonamide 579.40 [M + H]⁺ 14119

(R)-N-(3-(2-(2-aminopyrimidin- 5-yl)-8-ethyl-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 584.30 [M + H]⁺ 14 120

N-(3-(2-(6-aminopyridin-3-yl)-7- methoxy-4-morpholinoquinazolin-6-yl)-2- fluorophenyl)-3-fluoropropane-1-sulfonamide 569.30 [M − H]⁻ 16 121

3-fluoro-N-(2-fluoro-3-(2-(2- (methylamino)pyrimidin-5-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6- yl)phenyl)propane-1- sulfonamide557.3 [M + H]+ 13 122

N-(3-(2-(2- (ethylamino)pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 569.4[M − H]− 13 123

N-(3-(2-(6-(ethylamino)pyridin- 3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 570.4[M + H]+ 13 124

N-(5-(6-(2-fluoro-3-(3- fluoropropylsulfonamido) phenyl)- 8-methoxy-4-morpholinoquinazolin-2- yl)pyridin-2-yl)acetamide 613.3 [M + H]+ 9 125

N-(4-(6-(2-fluoro-3-(3- fluoropropylsulfonamido) phenyl)- 8-methoxy-4-morpholinoquinazolin-2- yl)phenyl)acetamide 612.3 [M + H]+ 9 126

3-fluoro-N-(2-fluoro-3-(8- methoxy-2-(4- (methylsulfonamido)phenyl)-4-morpholinoquinazolin-6- yl)phenyl)propane- 1-sulfonamide 646.4 [M − H]−9 127

(S)-N-(3-(2-(6-aminopyridin-3- yl)-4-(3- methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide 556.6[M + H]+ 13 128

(S)-N-(3-(2-(2-aminopyrimidin-5- yl)-4-(3- methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2- fluorophenyl)-3- fluoropropane-1- sulfonamide 557.3[M + H]+ 13 129

(S)-N-(3-(2-(6-amino-4- fluoropyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 574.3 [M + H]+ 13 130

(S)-N-(3-(2-(6-amino-4- methylpyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 570.2 [M + H]+ 13 131

(S)-N-(3-(2-(2-amino-4- methylpyrimidin-5-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 571.3 [M + H]+ 13 132

(S)-N-(3-(2-(2-amino-4- methylpyrimidin-5-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-2,5-difluorobenzenesulfonamide 623.1 [M + H]+ 13 133

3-fluoro-N-(2-fluoro-3-(2-(6-((2- methoxyethyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide 600.2 [M + H]+ 13 134

(R)-N-(3-(2-(6-amino-5- fluoropyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin- 6-yl)-2-fluorophenyl)-3fluoropropane-1-sulfonamide 603.1 [M + H]+ 9 135

(R)-N-(3-(2-(6-amino-4- fluoropyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin- 6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 603.3 [M + H]+ 9 136

(R)-3-fluoro-N-(2-fluoro-3-(8- methoxy-2-(2-(methylamino)pyrimidin-5-yl)-4- (3-methylmorpholino)quinazolin-6-yl)phenyl) propane-1-sulfonamide 600.1 [M + H]+ 9 137

(R)-N-(3-(2-(2-aminopyrimidin- 5-yl)-8-ethoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 600.3 [M + H]+ 10 138

(R)-N-(3-(8-ethoxy-2-(2- (methylamino)pyrimidin-5-yl)-4-(3-methylmorpholino)quinazolin- 6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 614.3 [M + H]+ 10 139

3-fluoro-N-(2-fluoro-3-(2-(4-(3- methylureido)phenyl)-4-morpholinopyrido[3,2- d]pyrimidin-6-yl) phenyl)propane- 1-sulfonamide598.3 [M + H]+ 13 140

(R)-N-(3-(2-(6-amino-4- fluoropyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2- d]pyrimidin-6-yl)-2- fluorophenyl)-3-fluoropropane-1- sulfonamide 574.3 [M + H]+ 13 141

(R)-N-(3-(2-(2-aminopyrimidin- 5-yl)-8-(2-fluoroethoxy)-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 618.2 [M + H]+ 10 142

(R)-N-(3-(2-(6-amino-5- fluoropyridin-3-yl)-8-(2- fluoroethoxy)-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 635.3 [M + H]+ 10 143

(R)-N-(3-(2-(5-aminopyrazin-2- yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6- yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide 586.4 [M + H]+ 9 144

(R)-N-(3-(2-(6-amino-4- cyanopyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin- 6-yl)-2-fluorophenyl)-3fluoropropane-1-sulfonamide 610.1 [M + H]+ 9

Example 145 A. B-RAF_(V600E) Radiometric Assay.

Compound inhibition for B-RAF_(V600E) was determined through radiometricassay using a BRAF enzyme (Catalog No. 14-557, Millipore, USA) andMEK-K97M protein as a substrate (Catalog No. 0785-0000-1, ProqQinaseGmbH, Germany). The B-RAF kinase catalyzes the phosphorylation of MEKprotein in the presence of gamma ATP (PLC-101, Jonaki, CCMB, Hyderabad),cold ATP and Mg²⁺.

The phosphorylated protein product is detected by the scintillationcounter Topcount® machine (Perkin Elmer). This assay has been adaptedfrom the method previously reported by Yeh et al. (2007, Clinical CancerResearch; 13, 1576-1583). The assay measures the B-RAF mediated transferof 32P from the gamma position of radiolabeled ATP onto MEK1-KD. Thelabeled phosphorylated protein was measured in MicroBeta Trilux Counter(Perkin Elmer). The assay was validated with reference compounds RAF1Kinase Inhibitor I and ZM 336372 inhibitor which are reported to beinhibitors of B-RAF enzyme (Lackey, 2000, Medicinal Chemistry Letters;10(3):223-226; Kupcho, “Fluorescent High throughput kinase cascadeassays for inhibitor characterization, RAF-MEK-ERK pathway,www.invitrogen.com, and Hall-Jackson, 1999, Chemical Biology;6(8):559-568). B-RAF enzyme mixture (13 L) was added to compound wellscontaining 2 L of the NCE in 1% DMSO and incubated for 45 min at rt on ashaking incubator at 300 rpm. MEK-K97M (0.5 jg) and cold ATP to a finalconcentration of 5 M, and hot ATP 0.1 μCi in a volume of 10 L was addedto each well and incubated for 2 h at rt on a shaking incubator at 300rpm. The reaction was stopped by addition of 8N HCl (13 μL) containingATP (1 mM: 495 μL 1N HCl and 5 μL 100 mM ATP). Aliquot (30 μL) was thentransferred to the center of a 2 cm×2 cm P81 paper. P81 paper was washed8×5 min each with ortho-phosphoric acid (0.5%). P81 papers are washedtwice with acetone for 5 min. Assay squares were allowed to dry for 15min at 37° C. P81 paper are transferred to Optiplate™ (Perkin Elmer) andcounted in a Topcount® counter (Perkin Elmer). Data was plotted againstthe compound concentration to generate dose-response curves and IC₅₀values were determined using a sigmoidal dose response curve fitGraphPad Prism® v5 software.

B. mTOR Kinase TR-FRET Assay

Compound inhibition for mTOR kinase was determined by homogeneousTR-FRET assay using ULight-p70 S6K (Thr 389) peptide as substrate. mTORenzyme (Millipore, US; 5 g) was used in the assay. The reaction bufferwas HEPES (50 mM, pH 7.5), EGTA (1 mM), and MnCl₂ (3 mM). Test compoundwas pre-incubated with mTOR for 30 min followed by 50 nM ULight-p70 S6K(Thr 389) peptide along with ATP (20 μM).

After incubating the reaction mixture for 30 min, Eu-labeledanti-phospho-substrate antibody (1 nM, Perkin Elmer, USA) was added.Fluorescence emission at 615 and 665 nM was measured upon excitation at340 nM. The compound dilution was carried out in 100% DMSO followed by abuffer dilution. The kinase reaction was incubated for 1 h at rtfollowed by the addition of substrate-ATP mix and incubated at rt for 1h. The reaction was terminated by the addition of EDTA followed by theaddition of detection mix. IC₅₀ values were determined using a sigmoidaldose response curve fit, GraphPad Prism® v5 software.

C. PI3 Kinase alpha TR-FRET Assay

Compound inhibition for PI3Kα was determined in a homogeneous TR-FRETassay using a PI3Kα assay kit (Millipore, US, Catalog #33-016). The PI3kinase catalyzes phosphorylation of phosphatidylinositol, 5-bisphosphate(PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3) in thepresence of ATP and Mg²⁺. The PIP3 product is detected by displacementof biotin-PIP3 from an energy transfer complex consisting of Europiumlabeled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology(PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC).Excitation of Europium in the complex results in an energy transfer tothe APC and a fluorescence emission at 665 nm.

Compounds tested were dissolved in DMSO and directly distributed into384-well plates at a volume of 0.5 μL. P110/P85a/PIP2 mixture (14.5 μL)was added to compound wells and incubated for 30 min at rt for 60 min.P110/P85a was expressed in SF9 cells and purified in-house. 5 ngP110/P85a was used in the assay. The kinase reaction was started by theaddition of ATP. The assay concentrations of both PIP2 and ATP were 40μM. The reaction mixture was incubated for 30 min and was terminated bythe addition of stop mix and detection mix. Fluorescence was measured at615 and 665 nm upon excitation at 340 nm in a Victor V5 fluorometer(Perkin Elmer, US). The fluorescence emission ratio at 665 to 615 nm,proportional to the kinase activity, was plotted against the compoundconcentration to generate dose-response curves and IC₅₀ values weredetermined.

D. XT T assay for Cell Viability:

Cell lines (A375 ATCC No. CRL-1619, A2058 ATCC No. CRL-11147 and RKOATCC No. CRL-2577, American Type Culture Collection (ATCC), ManassasVa.) once attaining 80% confluency were trypsinized, centrifuged andresuspended in fresh media. Cells (1000-2000/per well) were seeded in96-well plate and incubated over-night at 37° C. in a 5% CO₂ incubator.Compound dilutions were prepared in 100% DMSO followed by dilutions inthe respective media. The cells were treated with NCEs for 72 h at 37°C. in 5% CO₂ incubator. After 72 h, freshly prepared XTT (1 mg/ml)/PMS(25 μM) solution was added, incubated for 2 to 3 h at 37° C. and theabsorbance was measured at 450 nm using an ELISA plate reader. KeepingDMSO control as 100%, the effect of the compound to inhibit the cellproliferation was calculated and the GI₅₀ values were determined usingsigmoidal dose response curve fit in GraphPad Prism® v5 software.

E. Measurement of pERK, pS6RP, pAKT-S473, and pAKT-T308 by In CellWestern (ICW) assays

Cell lines A375, A2058 and RKO obtained from the ATCC as provided above,were grown, and after attaining 80% confluency were trypsinized,centrifuged and resuspended in fresh media. The cells were seeded at thespecified density (20,000 to 50,000) in a 96-well format black-wellclear bottom plate (Corning) and incubated overnight at 37° C. in a 5%CO₂ incubator. The next day, compound dilutions of test compounds wereprepared in 100% DMSO followed by dilutions in respective media.Treatment of test compounds was performed for 3 h at 37° C. in 5% CO₂incubator. Following 3 h drug treatment, the conditional media wasdiscarded and the cells were washed once with cPBS (PBS containing 0.1%magnesium chloride hexahydrate and 0.1% anhydrous calcium chloride) andfixed with 4% paraformaldehyde in cPBS for 1 h at rt. After fixing, thecells were given three washes using cPBST (cPBS containing 0.1% Triton™X-100 reagent) and then blocked using blocking solution (5% skimmed milkpowder or 5% BSA prepared in cPBST) for 2 h at rt with shaking at 300rpm. The cells were again washed thrice with cPBST and incubated withprimary antibody phospho-p44/42 MAPK(Erk1/2)(Thr202/204) antibody (CellSignaling, Catalog #9101L), phospho S6 ribosomal protein (CellSignaling, Catalog #4858L), phospho AKT (Thr 308) (Cell Signaling,Catalog #9275) or phospho AKT (Ser 473) (Cell Signaling, Catalog #4060L)in specified dilutions (1:500-1:2500), prepared in respective blockingsolutions, in a racker overnight at 4° C. The next day, the cells werewashed with 1× Delfia® wash buffer (4×1 wash) and incubated withsecondary antibody (Delfia®-Eu-N1 labeled anti-rabbit antibody;PerkinElmer, Catalog #AD0105; dilutions: 1:2000 to 1:6000 in Delfia®assay buffer (PerkinElmer, Catalog #1244-111)) for 2 h at rt in the darkat 300 rpm. The cells were then given four washes with 1× Delfia® washbuffer and incubated with Wallac Delfia® Enhancement solution (100 μL;PerkinElmer, Catalog #1244-105) for 20 min at rt in the dark at 300 rpm.The fluorescence emission was then read at 615 nM with an excitationwavelength of 340 nM using a Victor V5 Fluorometer (Perkin Elmer, US).The cells were then washed once with 1×cPBS and incubated with 100 μL of0.5 mg/mL of Hoechst 33258 dye prepared in cPBS and read at 460 nm with355 nm excitation, thereby evaluating the correction factor.

PLX-4032 (B-RAF inhibitor), BEZ-235 (PI3K/mTOR inhibitor) and GDC-0941(PI3K inhibitor) were taken as the standards for pERK, pS6RP/pAKT (S473)and pAKT (T308) inhibitions, respectively, as are shown in the followingTable. The % inhibition for the test compounds of formula (I)(newchemical entities (NCEs)) was calculated keeping DMSO control as 0% andthe IC₅₀ values were determined using sigmoidal dose response curve fitin GraphPad Prism® v5 software.

Avg Reading range- Relative Fluorescent Units Analytes Group Conc (RFU)% Inhibition A375-pERK Background No cells  500-1000 — inhibitionPositive 0.1% 50000-90000 0.0 control DMSO Standard PLX-  3000-1000085%-90% 4032(10 mM) NCE's 10 mM  2000-10000 85%-90% RKO-pERK BackgroundNo cells  500-1000 — inhibition Positive 0.1% 50000-90000 0.0 controlDMSO Standard PLX-  8000-10000 75%-85% 4032(10 mM) NCE's 10 mM 8000-10000 80%-90% RKO-pS6RP Background No cells 1000-2000 — inhibitionPositive 0.1% 40000-80000 0.0 control DMSO Standard BEZ-  4000-1600080%-90% 235(10 mM) NCE's 10 mM  2000-12000 70%-95% RKO- Background Nocells  700-1000 — pAKT(Ser473) Positive 0.1% 50000-60000 0.0 inhibitioncontrol DMSO Standard BEZ- 5000-9000 80%-90% 235(10 mM) NCE's 10 mM 4000-20000 85%-90% RKO- Background No cells  500-5000 — pAKT(Thr308)Positive 0.1% 30000-80000 0.0 inhibition control DMSO Standard GDC- 2000-30000 55%-65% 0941(10 mM) NCE's 10 mM 10000-30000 50%-70%

Data from the B-RAF radiometric assay, the PI3K and mTOR TR-FRET assays,the XTT cell viability assays and the in-cell Western assays forExamples 1-120 are shown in Table 3.

TABLE 3 Kinase assay A375 cells RKO cells Ex B-Raf PI3Kα mTOR pERK XTTpERK pS6RP pAKT (T308) XTT   1 A A B B B C   2 A B B B   3 A B A C    4B B   5 A A A A A A B   6 A A B B   7 B A B B B B   8 B B B B B   9 A BB B  10 B B  11 A B A A B B B  12 B A C  13 A B B B  14 B A B B  15 B BB B  16 B B B  17 A A B B  18 B B B B  19 A B B B  20 A B B B  21 B B BC  22 A B A B  23 B B  24 B B  25 B B B  26 B B B B  27 A B A B  28 A BA B  29 A B A B  30 A B A B A B B  31 B B  32 B A B  33 B B B B  34 B A 35 A B  36 A B A B C  37 A B A B C  38 A B A B  39 A B A A A  40 A A AB B  41 A A A B  42 A A A A A B B  43 A B A A A A B B  44 B B  45 B B BB  46 A B A B  47 A B B B  48 A B  49 A B  50 A A A A B  51 A A A A B 52 A B A A A B B  53 A A A A B  54 A B A B  55 A B A A A B B  56 A B AA  57 A B A  58 A A B  59 B A  60 A A C C  61 A B  62 A A A A B  63 A AA A A B B  64 A B A A B  65 A A A B B B  66 A B  67 A A B B A  68 A A AB B  69 A B A A A  70 A B B A  71 B A A B  72 A A  73 A A A A A B B  74A B  75 A A A B  76 A B B B  77 A B B B  78 A B A B  79 A B A A A B B B 80 A B B B  81 A B A B  82 A B A A  83 A B  84 A B  85 A B  86 B A A BB B  87 A A A B B B B B  88 A A A B B B B B B  89 A B B  90 A B B B B 91 A A A  92 A A B A A B C C  93 A A B B B C B  94 A A A A B A B B B 95 A B A B B C  96 A B B A A A B B  97 A A B A B B B  98 A A B  99 A BA A B A B B 100 A A B B A B B 101 A A B A B B A B B 102 A A A B B B B B103 A B B C C 104 A A A A B 105 A A B B B C C 106 A A A C B 107 A B 108A A B A B B C B 109 A A A B B C 110 A B A C 111 A B A B B 112 A B 113 AA A A B C B 114 A B A B B 115 A B B 116 A B B A A 117 A A A B C 118 A BB C 119 A B 120 A B A A B 121 A A B B 122 A B 123 A A A 124 A B 125 B AA 126 B B 127 B A A B 128 A A B B 129 A A A B B 130 B A B B 131 B A B B132 A A B B 133 A B 134 A C A A A A A B 135 A C A A A A B B 136 A B A B137 A B A B A A 138 A B 139 A A B B B B B 140 A B B B A B 141 A B 142 AB 143 A B 144 A B A: IC₅₀ = 1-100 nM B: IC₅₀ = >100-1000 nM C: IC₅₀= >1000-10000 nM

Example 146: Protein Biomarkers for Monitoring Inhibition ofRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR Pathways

The compounds described herein were tested for their ability to inhibita combination of various biomarkers (pERK, pS6RP, pS6K, pAKT-S473 andpAKT-T308) in vitro in cultured cells and also in lysates made fromtumor samples. Representative results are shown in the FIGURE, where thedecrease in the phosphorylation of the various biomarkers in tumor celllysates from mice was assessed on a Western blot. Biochemical analysiswas done according to the protocols provided by the antibody providersas described in detail in Example 89E. For the experiment shown in TheFIGURE, mice bearing the tumors derived from a colon cancer cell lineRKO were treated with a compound of the invention for 4 hours (for pERK1/2 and pS6RP analytes) or for 8 hours (for pAKT-S473 and pAKT-T308analytes). The tumors were then excised, lysed and analyzed for thetotal and phospho-protein levels on a Western blot. Each lane representsthe lysate from the tumor derived from a single animal, and there werefour animals per treatment group. The percent inhibition ofphospho-protein signal is indicated above each lane. Panel A). Total andphospho-protein levels of ERK protein. Panel B). Total andphospho-protein levels of S6 protein. Panel C). Total andphospho-protein (S473) levels of AKT. Panel D). Total andphospho-protein (T308) levels of AKT. The decrease in the signal of theband corresponding to a given phospho-protein indicates an inhibitoryeffect of the compound on the target protein.

All publications cited in this specification are incorporated herein byreference. While the invention has been described with reference toparticular embodiments, it will be appreciated that modifications can bemade without departing from the spirit of the invention. Suchmodifications are intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A dosing regimen comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I):

wherein: X is CH or N; Y is H, optionally substituted C₁-C₆ alkyl, OR¹or NR²R³; T is H or C₁-C₆ alkoxy; R¹ is optionally substituted C₁-C₆alkyl, optionally substituted (C₁-C₆ alkyl)OH, optionally substituted(C₁-C₆ alkyl)OC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₆ alkyl)NH₂, optionally substituted (C₁-C₆alkyl)CO₂H, or optionally substituted (C₁-C₆ alkyl)CONH₂; R² and R³ arejoined to form an optionally substituted heterocycle; R⁴ is optionallysubstituted morpholine; R⁶ is optionally substituted aryl or optionallysubstituted heteroaryl; R⁷ is optionally substituted aryl, optionallysubstituted C₁-C₆ alkyl, or optionally substituted heteroaryl; B is H orhalogen; and R^(8′) is halogen.
 2. The dosing regimen according to claim1, wherein the administration of the compound regulates at least one ofRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways.
 3. The dosing regimenaccording to claim 1, wherein the compound is administered to thepatient orally, by injection, inhalation (including orally, intranasallyand intratracheally), ocularly, transdermally, intravascularly,subcutaneously, intramuscularly, sublingually, intracranially,epidurally, rectally, or vaginally.
 4. The dosing regimen according toclaim 1, wherein the compound is administered to the patient about every2 hours, about every 6 hours, about every 8 hours, about every 12 hours,about every 24 hours, about every 36 hours, about every 48 hours, aboutevery 72 hours, about every week, about every two weeks, about everythree weeks, about every month, or about every two months.
 5. The dosingregimen according to claim 1, wherein: R⁴ is morpholine substituted byC₁-C₆ alkyl; R⁶ is:

wherein: M is N or CR¹⁰; Q is N or CR¹³; Z is N or CR¹⁴; R¹⁰ is H, C₁-C₆alkyl, halogen, CN or CF₃; R¹² to R¹⁴ are, independently, H, halogen,C₁-C₆ alkyl, or CF₃; R¹⁷ is NHC(O)NHNR⁹, H, C₁-C₆ alkyl, (C₁-C₆alkyl)-NH₂ or (C₁-C₆ alkyl)-OH, (C₁-C₆ alkyl)-O—(C₁-C₆ alkyl), CO(C₁-C₆alkyl) or SO₂(C₁-C₆ alkyl); or R¹³ and R¹⁷ or R¹⁴ and R¹⁷ are joined toform an optionally unsaturated ring; R⁹ is C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, or heteroaryl; and R¹⁵ is C₁-C₆ fluoroalkyl or C₁-C₆hydroxyalkyl; and R⁷ is phenyl substituted by one or more halogen, C₁-C₆alkyl optionally substituted by one or more F, or thiophene.
 6. Thedosing regimen according to claim 1, wherein R⁶ is:

wherein: Z is CH or N; and R⁹ is C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, orheteroaryl.
 7. The dosing regimen according to claim 1, wherein R⁶ is anoptionally substituted pyrimidine, optionally substituted pyridine,optionally substituted pyrrole[2,3-b]pyridine, optionally substitutedindazole or optionally substituted benzimidazole.
 8. The dosing regimenaccording to claim 1, wherein R⁶ is:

wherein: R¹⁰ is H, C₁-C₆ alkyl or CF₃; and R¹⁷ is H, C₁-C₆ alkyl, (C₁-C₆alkyl)-NH₂ or (C₁-C₆ alkyl)-OH.
 9. The dosing regimen according to claim1, wherein R⁶ is:

wherein: R¹, R¹² and R¹³ are, independently, H, halogen, C₁-C₆ alkyl, CNor CF₃; and R¹⁷ is H, C₁-C₆ alkyl, (C₁-C₆ alkyl)-NH₂ or (C₁-C₆alkyl)-OH; or R¹³ and R¹⁷ are joined to form an optionally unsaturated5-membered ring.
 10. The dosing regimen according to claim 1, whereinthe compound is selected from the group consisting of:2,6-difluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)benzenesulfonamide;N-(3-(2-(1H-indazol-4-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-((2-aminoethyl)amino)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(2-fluoro-3-(2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;2,6-difluoro-N-(2-fluoro-3-(2-(4-(3-(2-hydroxyethyl)ureido)phenyl)-8-methoxy-4-morpholinoquinazolin-6-yl)phenyl)benzenesulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;2,6-difluoro-N-(2-fluoro-3-(8-methoxy-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl)phenyl)benzenesulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-amino-2-fluoropyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2-methylpropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)ethanesulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)butane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,4-difluorobenzenesulfonamide;N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(6-amino-5-methylpyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2-fluorobenzenesulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(3-methylureido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-2-sulfonamide;N-(2-fluoro-3-(8-methoxy-4-morpholino-2-(4-(3-(pyridin-4-yl)ureido)phenyl)quinazolin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(2-amino-4-methylpyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(1H-indazol-4-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)thiophene-2-sulfonamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(6-(3-methylureido)pyridin-3-yl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl)phenyl)propane-1-sulfonamide;(S)—N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)-3-fluoro-N-(2-fluoro-3-(8-methoxy-4-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl)phenyl)propane-1-sulfonamide;(S)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-2-fluorobenzenesulfonamide;N-(3-(2-(6-amino-5-chloropyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-4-morpholino-2-(6-(propylamino)pyridin-3-yl)quinazolin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(6-(methylamino)pyridin-3-yl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(2-(methylamino)pyrimidin-5-yl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-ethoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-(cyclopentyloxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-ethoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-isopropoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(8-(2-aminoethoxy)-2-(6-aminopyridin-3-yl)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-(cyclopropylmethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-(2-hydroxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;2-((2-(6-aminopyridin-3-yl)-6-(2-fluoro-3-(3-fluoropropylsulfonamido)phenyl)-4-morpholinoquinazolin-8-yl)oxy)aceticacid 2,2,2-trifluoroacetate;2-((2-(6-aminopyridin-3-yl)-6-(2-fluoro-3-(3-fluoropropylsulfonamido)phenyl)-4-morpholinoquinazolin-8-yl)oxy)acetamide;(R)—N-(3-(8-ethoxy-4-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-aminopyridin-3-yl)-8-(cyclopentyloxy)-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-aminopyridin-3-yl)-8-isopropoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-isopropoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(6-aminopyridin-3-yl)-8-ethoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-ethoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-(2-methoxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-(2-methoxyethoxy)-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-4,8-dimorpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4-morpholino-8-(pyrrolidin-1-yl)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-8-(pyrrolidin-1-yl)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-aminopyridin-3-yl)-4-(3-methylmorpholino)-8-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-4-(3-methylmorpholino)-8-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-aminopyridin-3-yl)-4-(3-methylmorpholino)-8-(pyrrolidin-1-yl)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-2,6-difluorobenzenesulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-2,6-difluorobenzenesulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-4-chloro-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(1H-indazol-4-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoropropane-1-sulfonamide;N-(2,4-difluoro-3-(8-methoxy-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-6-yl)phenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-2,4-difluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methoxy-4-morpholinoquinazolin-6-yl)-4-chloro-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(1H-indazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-5-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;(R)—N-(3-(2-(6-aminopyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;3-fluoro-N-(2-fluoro-3-(2-(6-((2-hydroxyethyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-4-methylpyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-4-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-5-chloropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;N-(3-(2-(6-amino-5-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide;(R)—N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(2-(2-((3-hydroxypropyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(2-(6-((3-hydroxypropyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(4-morpholino-2-(2-(propylamino)pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(2-(6-(methylamino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(2-(6-(isopropylamino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(4-morpholino-2-(6-(propylamino)pyridin-3-yl)pyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(2-aminopyrimidin-5-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(1H-indazol-4-yl)-8-methyl-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-ethyl-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-aminopyridin-3-yl)-7-methoxy-4-morpholinoquinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(2-(2-(methylamino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;N-(3-(2-(2-(ethylamino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(3-(2-(6-(ethylamino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;N-(5-(6-(2-fluoro-3-(3-fluoropropylsulfonamido)phenyl)-8-methoxy-4-morpholinoquinazolin-2-yl)pyridin-2-yl)acetamide;N-(4-(6-(2-fluoro-3-(3-fluoropropylsulfonamido)phenyl)-8-methoxy-4-morpholinoquinazolin-2-yl)phenyl)acetamide;3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(4-(methylsulfonamido)phenyl)-4-morpholinoquinazolin-6-yl)phenyl)propane-1-sulfonamide;(S)—N-(3-(2-(6-aminopyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(2-aminopyrimidin-5-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(6-amino-4-fluoropyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(6-amino-4-methylpyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(2-amino-4-methylpyrimidin-5-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(S)—N-(3-(2-(2-amino-4-methylpyrimidin-5-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide;3-fluoro-N-(2-fluoro-3-(2-(6-((2-methoxyethyl)amino)pyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;(R)—N-(3-(2-(6-amino-5-fluoropyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-amino-4-fluoropyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)-3-fluoro-N-(2-fluoro-3-(8-methoxy-2-(2-(methylamino)pyrimidin-5-yl)-4-(3-methylmorpholino)quinazolin-6-yl)phenyl)propane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-ethoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(8-ethoxy-2-(2-(methylamino)pyrimidin-5-yl)-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;3-fluoro-N-(2-fluoro-3-(2-(4-(3-methylureido)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)phenyl)propane-1-sulfonamide;(R)—N-(3-(2-(6-amino-4-fluoropyridin-3-yl)-4-(3-methylmorpholino)pyrido[3,2-d]pyrimidin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(2-aminopyrimidin-5-yl)-8-(2-fluoroethoxy)-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(6-amino-5-fluoropyridin-3-yl)-8-(2-fluoroethoxy)-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;(R)—N-(3-(2-(5-aminopyrazin-2-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide;and(R)—N-(3-(2-(6-amino-4-cyanopyridin-3-yl)-8-methoxy-4-(3-methylmorpholino)quinazolin-6-yl)-2-fluorophenyl)-3-fluoropropane-1-sulfonamide.11. The dosing regimen according to claim 1, wherein the compound is asalt of an acid or base.
 12. The dosing regimen according to claim 11,wherein said acid salt is selected from the group consisting of acetic,propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic acid, trifluoroacetic, and camphorsulfonic.
 13. Thedosing regimen according to claim 11, wherein said base salt is selectedfrom the group consisting of sodium, lithium, potassium,monomethylammonium, dimethylamonium, trimethylammonium,monoethylammonium, diethylammonium, triethylammonium,monopropylammonium, dipropylammonium, tripropylammonium,ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpholinium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-,di- and triethanolammonium, ethyl diethanolammonium,n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, andphenylmonoethanolammonium.
 14. The dosing regimen according to claim 1,wherein said co-regulation comprises inhibition of the RAS/RAF/MEK/ERKpathway.
 15. The dosing regimen according to claim 1, wherein saidco-regulation comprises inhibition of the PI3K/AKT/PTEN/mTOR pathway.16. The dosing regimen according to claim 1, wherein said co-regulationcomprises inhibition of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTORpathways.
 17. A kit comprising: at least one dosage form comprising acompound of formula (I):

wherein: X is CH or N; Y is H, optionally substituted C₁-C₆ alkyl, OR¹or NR²R³; T is H or C₁-C₆ alkoxy; R¹ is optionally substituted C₁-C₆alkyl, optionally substituted (C₁-C₆ alkyl)OH, optionally substituted(C₁-C₆ alkyl)OC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₆ alkyl)NH₂, optionally substituted (C₁-C₆alkyl)CO₂H, or optionally substituted (C₁-C₆ alkyl)CONH₂; R² and R³ arejoined to form an optionally substituted heterocycle; R⁴ is optionallysubstituted morpholine; R⁶ is optionally substituted aryl or optionallysubstituted heteroaryl; R⁷ is optionally substituted aryl, optionallysubstituted C₁-C₆ alkyl, or optionally substituted heteroaryl; R⁸ is Hor halogen; and R^(8′) is halogen; or a pharmaceutically acceptable saltthereof; and therapeutic instructions for regulating at least one ofRAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways, wherein the therapeuticinstructions comprise the steps of: administering to a patient in needthereof the compound of formula (I).
 18. The kit according to claim 17,wherein the compound is administered to the patient orally, byinjection, inhalation (including orally, intranasally andintratracheally), ocularly, transdermally, intravascularly,subcutaneously, intramuscularly, sublingually, intracranially,epidurally, rectally, or vaginally.
 19. The kit according to claim 17,wherein the compound is administered to the patient about every 2 hours,about every 6 hours, about every 8 hours, about every 12 hours, aboutevery 24 hours, about every 36 hours, about every 48 hours, about every72 hours, about every week, about every two weeks, about every threeweeks, about every month, or about every two months.
 20. A kitcomprising: at least one dosage form comprising a compound of formula(I):

wherein: X is CH or N; Y is H, optionally substituted C₁-C₆ alkyl, OR¹or NR²R³; T is H or C₁-C₆ alkoxy; R¹ is optionally substituted C₁-C₆alkyl, optionally substituted (C₁-C₆ alkyl)OH, optionally substituted(C₁-C₆ alkyl)OC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₆ alkyl)NH₂, optionally substituted (C₁-C₆alkyl)CO₂H, or optionally substituted (C₁-C₆ alkyl)CONH₂; R² and R³ arejoined to form an optionally substituted heterocycle; R⁴ is optionallysubstituted morpholine; R⁶ is optionally substituted aryl or optionallysubstituted heteroaryl; R⁷ is optionally substituted aryl, optionallysubstituted C₁-C₆ alkyl, or optionally substituted heteroaryl; R⁸ is Hor halogen; and R^(8′) is halogen; or a pharmaceutically acceptable saltthereof; and therapeutic instructions for treating cancer, wherein thetherapeutic instructions comprise the steps of: administering to apatient in need thereof the compound of formula (I).